CN108138237B

CN108138237B - Assessment of NFkB cell signaling pathway activity using mathematical modeling of target gene expression

Info

Publication number: CN108138237B
Application number: CN201680056337.1A
Authority: CN
Inventors: H·J·范奥义任
Original assignee: Koninklijke Philips NV
Current assignee: Koninklijke Philips NV
Priority date: 2015-08-14
Filing date: 2016-08-12
Publication date: 2022-04-05
Anticipated expiration: 2036-08-12
Also published as: US20170046477A1; BR112018002848A2; US20230260595A1; CA2995520A1; DK3334837T3; ES2861400T3; CN108138237A; AU2016309659A1; JP2018522575A; US11450409B2; EP3334837A1; WO2017029215A1; JP7028763B2; EP3334837B1

Abstract

The present invention relates to a method comprising inferring activity of an NFkB cellular signaling pathway based at least on measured expression levels of six or more target genes of the NFkB cellular signaling pathway in a sample. The invention also relates to an apparatus comprising a digital processor configured to perform such a method, a non-transitory storage medium storing instructions executable by a digital processing device to perform such a method, and a computer program comprising program code means to cause a digital processing device to perform such a method. The invention also relates to a kit for measuring expression levels.

Description

Assessment of NFkB cell signaling pathway activity using mathematical modeling of target gene expression

Technical Field

The present invention relates generally to the fields of bioinformatics, genomic processing, proteomic processing, and related fields. More specifically, the present invention relates to a method comprising inferring activity of an NFkB cellular signaling pathway based at least on measured expression levels of six or more target genes of the NFkB cellular signaling pathway in a sample. The invention also relates to an apparatus comprising a digital processor configured to perform such a method, a non-transitory storage medium storing instructions executable by a digital processing device to perform such a method, and a computer program comprising program code means to cause a digital processing device to perform such a method. The invention further relates to a kit for measuring expression levels.

Background

Genomics and proteomics analysis have substantial implementation and potential promise for clinical applications in the medical field, such as oncology, where a variety of cancers are known to be associated with specific combinations of genomic mutations/variations and/or high or low expression levels of specific genes, which play a role in the growth and evolution of cancers, such as cell proliferation and metastasis.

The nuclear factor-kappaB (NFkB or NF-. kappa.B) is an inducible transcription factor that regulates the expression of many genes involved in immune responses. The NFkB cell signaling pathway is a key cell signaling pathway involved in immune, inflammatory and acute phase responses, but is also involved in the control of cell survival, proliferation and apoptosis. In healthy non-activated cells, NFKB cell signaling pathway-associated transcription factors consisting of dimers derived from five genes (NFKB1 or p50/p105, NFKB2 or p52/p100, RELA or p65, REL and RELB) are predominantly cytoplasmic transcription factors due to their interaction with NFKB inhibitors (IkB) and thus maintain transcriptional inactivation, thus maintaining NFKB cell signaling pathway inactivation. Upon activation of the upstream signaling cascade, IkB becomes phosphorylated and undergoes ubiquitin-dependent degradation by the proteasome, and the NFkB dimer translocates into its nucleus, which is a transcription factor. In addition to this classical NFkB cell signaling pathway, there is an alternative pathway that can initiate NFkB-regulated transcription (see fig. 1; CP ═ classical pathway; AP ═ alternative pathway; PS ═ proteasome; NC ═ nucleus). The term "NFkB cell signaling pathway" herein preferably refers to any signaling process leading to the transcriptional activity of the above-mentioned NFkB transcription factor.

Although the activity of the NFkB cell signaling pathway is known to be associated with different types of cancer and supports the pro-active phenotype of cancer cells, there are no clinical assays available to assess NFkB cell signaling pathway activity. It would therefore be desirable to be able to improve the possibility of identifying patients suffering from cancer, such as diffuse large B-cell lymphoma (DLBCL), multiple myeloma, another cancer of hematological origin, or a solid tumor such as breast, melanoma or prostate tumor, which is at least partially driven by a deregulated NFkB cell signalling pathway and thus likely to respond to inhibitors of the NFkB cell signalling pathway.

Xing, F.ZHou and J.Wang, "Subset of genes targeted by transcription factors NF-. kappa.B in TNF α -stimulated human HeLa cells", Functional and Integrated genetics, Vol.13, No.1, pages 143to 154(2013) revealed a study claiming identification of the Direct Target Gene (DTG) of NF-. kappa.B in TNF α -stimulated HeLa cells by using ChIP-Seq, RNAi and gene expression profiling techniques.

Feuerhake et al, "NF κ B activity, function, and target-gene signatures in primary mediated large B-cell lymphoma and diffuse large B-cell lymphoma", Blood, Vol.106, No.4, pages 1392to 1399(2005) revealed that primary mediastinal large B-cell lymphoma (MLBCL) shares clinical and molecular features with traditional Hodgkin's lymphoma, including the nuclear localization of the nuclear factor κ B (NF κ B) subunit c-REL (reticuloendotheliosis virus oncogene homolog) in the experimental series. The authors analyzed the c-REL subcellular localization in otherwise primary MLBCL and identified NF κ B activity and function in MLBCL cell lines.

US 2004/0180341A1 relates to the transcriptional regulation of a family of proteins defined by the presence of the RKIP motif. Proteins comprising the RKIP motif regulate kinases involved in signal transduction pathways. Transcriptional regulation of RKIP motif-containing proteins underlies screening assays for identifying substances useful in the modulation of signal transduction pathways subject to RKIP family mediated regulation, as well as the diagnosis and treatment of diseases involving inappropriate activity of pathways subject to RKIP family mediated regulation.

Summary of The Invention

The present invention provides new and improved methods and apparatus as disclosed herein.

According to one main aspect of the present invention, the above problem is solved by a method for inferring the activity of the NFkB cellular signaling pathway using mathematical modeling of target gene expression, said method comprising:

inferring activity of the NFkB cell signaling pathway based at least on expression levels of six or more, e.g., seven, eight, nine, ten, eleven, or twelve or more target genes of the NFkB cell signaling pathway measured in the sample, wherein the inferring comprises:

determining a level of an NFkB Transcription Factor (TF) element in the sample, the NFkB TF element controlling transcription of six or more target genes of the NFkB cellular signaling pathway, the determining based at least in part on evaluating a mathematical model that correlates expression levels of the six or more target genes of the NFkB cellular signaling pathway with the level of the NFkB TF element, wherein the six or more target genes are selected from the group consisting of: BCL2L1, BIRC3, CCL2, CCL3, CCL4, CCL5, CCL20, CCL22, CX3CL1, CXCL1, CXCL2, CXCL3, ICAM1, IL1B, IL6, IL8, IRF1, MMP9, NFKB2, NFKBIA, NFKBIE, PTGS2, SELE, STAT5A, TNF, TNFAIP2, TNIP1, TRAF1, and VCAM 1;

inferring activity of the NFkB cellular signaling pathway based on the determined level of the NFkB TF element in the sample,

wherein the inferring is performed by a digital processing device using the mathematical model.

In this context, "level" of a TF element refers to the level of activity of the TF element with respect to transcription of its target gene.

The present invention is based on the recognition by the inventors that a suitable way of identifying effects occurring in the NFkB cellular signaling pathway can be based on measuring the signal output of the NFkB cellular signaling pathway, which is in particular transcribed through a target gene of the NFkB Transcription Factor (TF) element controlled by the NFkB cellular signaling pathway. This recognition by the present inventors assumes that the TF level in the sample is in a quasi-steady state, which can be detected, in particular, by the expression value of the target gene. The NFkB cell signaling pathway targeted herein is known to be associated with different types of cancer and supports the pro-active phenotype of cancer cells, as the NFkB cell signaling pathway is known to regulate genes that control cell proliferation and cell survival processes. Many different types of human tumors were found to have deregulated NFkB cell signaling pathway activity. In addition, studies have shown that inhibiting the activity of the constitutive NFkB cell signaling pathway can block the oncogenic potential of cancer cells.

The invention makes it possible to determine the activity of the NFkB cellular signalling pathway by: (i) determining a level of an NFkB TF element in a sample, wherein the determining is based at least in part on evaluating a mathematical model that correlates the expression level of six or more target genes that are transcribed to an NFkB cellular signaling pathway controlled by the NFkB TF element with the level of the NFkB TF element, and (ii) inferring an activity of the NFkB cellular signaling pathway based on the determined level of the NFkB TF element in the sample. This preferably allows for an improved possibility of identifying patients with cancer, such as diffuse large B-cell lymphoma (DLBCL), multiple myeloma, another cancer of hematological origin, or a solid tumor such as breast, melanoma or prostate tumor, which is at least partially driven by a deregulated NFkB cell signaling pathway and thus likely to be responsive to inhibitors of the NFkB cell signaling pathway. An important advantage of the present invention is that it allows determining the activity of the NFkB cellular signalling pathway using a single sample, without the need for multiple samples taken at different time points.

Herein, an NFkB Transcription Factor (TF) element is defined as a protein complex containing at least one or preferably a dimer of NFkB members (NFkB1 or p50/p105, NFkB2 or p52/p100, RELA or p65, REL and RELB) capable of binding to a specific DNA sequence, thereby controlling transcription of a target gene.

The mathematical model may be a probabilistic model, preferably a bayesian network model, based at least in part on conditional probabilities relating the NFkB TF element to the expression levels of six or more target genes of the NFkB cellular signaling pathway measured in the sample, or the mathematical model may be based at least in part on one or more linear combinations of the expression levels of six or more target genes of the NFkB cellular signaling pathway measured in the sample. In particular, it is concluded that the activity of the NFkB cell signaling pathway can be performed as described in published International patent application WO2013/011479A2 ("association of cellular signaling pathway activity using basic modulation of target gene expressions") or as described in published International patent application WO2014/1026868A2 ("association of cellular signaling pathway activity combining(s) of target gene expressions"), which are hereby incorporated by reference in their entirety. Further details regarding the use of mathematical models of target gene expression to infer cell signaling pathway activity can be found in Verhaegh W.et al, "Selection of qualified pathway therapy through the use of knowledge-based regulatory models through pathways," Cancer Research, Vol.74, No.11,2014, 2936-.

The use of probabilistic models, such as bayesian network models, allows the integration of existing information about the NFkB cellular signaling pathway using conditional probability relationships. This also includes the integration of information based on partial (rather than comprehensive) knowledge of the NFkB cell signaling pathway and biological measurements typically measured with some uncertainty. In contrast, using a mathematical model based at least in part on one or more linear combinations of expression levels may provide a very simple and easily calculated way to infer the activity of the NFkB cellular signaling pathway.

If the sample is a sample of a subject, the inferred activity of the NFkB cellular signaling pathway may be associated with the subject, in particular a tissue and/or a cell and/or a body fluid of the subject, wherein the term "subject" as used herein refers to any living organism. In some embodiments, the subject is an animal, preferably a mammal. In certain embodiments, the subject is a human, preferably a medical subject. On the other hand, if the sample is taken from, for example, a cell line, primary cell culture or a tissue culture, the inferred activity is only representative of the subject having a possible treatment effect when the original sample from which the cell line, primary cell culture or tissue culture was derived was extracted from the subject and in case the cell line, primary cell culture or tissue culture was subjected to one or more treatments (e.g., with a drug, chemical or physical treatment). Furthermore, a "target gene" can be a "direct target gene" and/or an "indirect target gene" (as described herein).

Particularly suitable target genes are described in the text paragraphs below and in the examples below (see, e.g., table 1).

Thus, according to a preferred embodiment, the target gene is selected from the group consisting of the target genes listed in table 1.

Particularly preferred is a method wherein the six or more target genes are selected from the group consisting of: CXCL2, ICAM1, IL6, CCL5, NFKBIA, IL8, TNFAIP2, CXCL3, MMP9, NFKB2, CCL20, CCL2, CXCL1, TNF, IRF1, TRAF1, NFKBIE, VCAM1 and BIRC3, preferably wherein six or more target genes comprise three or more, e.g. four, five, six, seven, eight or nine or more target genes selected from the group consisting of: CXCL2, ICAM1, IL6, CCL5, NFKBIA, IL8, TNFAIP2, CXCL3, MMP9, NFKB2, CCL20, CCL2 and CXCL1, more preferably the three or more target genes are selected from the group consisting of: CXCL2, ICAM1, IL6, CCL5, NFKBIA, IL8 and TNFAIP 2.

These target genes were selected based on a novel methodology of extensive literature review by the inventors, indicating that the selected target genes provide a good basis for inferring the activity of the NFkB cell signaling pathway, as detailed in example 2. Advantageously, since multiple target genes are used to infer the activity of the NFkB cellular signaling pathway, a more robust inference of the activity of the NFkB cellular signaling pathway can be achieved.

Another aspect of the invention relates to a method (as described herein), further comprising:

determining whether the NFkB cellular signaling pathway is operating abnormally based on the inferred activity of the NFkB cellular signaling pathway.

By determining whether an NFkB cell signaling pathway functions abnormally, for example, in patients with cancer that is driven at least in part by a deregulated NFkB cell signaling pathway, these patients can be identified in an efficient and reliable manner. In another variation, the methods (as described herein) can be used to identify cell lines derived, for example, from a cancer patient sample, with or without the use of a particular stimulating agent, such as TNF α or LPS.

The present invention also relates to a method (as described herein) further comprising:

it is proposed to prescribe a drug for correcting abnormal operation of NFkB cell signaling pathway,

wherein the recommendation is made only if the NFkB cellular signaling pathway is determined to be abnormally operational based on the inferred activity of the NFkB cellular signaling pathway.

By doing so, it can be better ensured that e.g. drugs relying on inhibitors of the NFkB cell signalling pathway are recommended only to patients with cancers that are likely to respond to these inhibitors. In this way, unnecessary ingestion of these drugs by patients who may not benefit from them can be avoided, while the chances of therapeutic response are optimized.

The invention also relates to a method (as described herein), wherein said inferring comprises:

inferring activity of the NFkB cellular signaling pathway based at least on expression levels of six or more target genes in a set of target genes of the NFkB cellular signaling pathway measured in the sample.

Advantageously, since multiple target genes are used to infer the activity of the NFkB cellular signaling pathway, a more robust inference of the activity of the NFkB cellular signaling pathway can be achieved.

The sample used according to the present invention may be an extracted sample, i.e. a sample that has been extracted from a subject. Examples of samples include, but are not limited to, tissue, biopsy, cells, blood, and/or bodily fluids of a subject. It may be, for example, obtained from a cancer lesion or suspected cancer lesion, or from a metastatic tumor, or from a body cavity in which the liquid present is contaminated with cancer cells (e.g. the pleural or abdominal or bladder cavity), or from other body fluids containing cancer cells, etc., preferably obtained by biopsy procedures or other sample extraction procedures. The cells extracted from the sample may also be tumor cells from a hematologic malignancy (e.g., leukemia or lymphoma). In some cases, the cell sample may also be circulating tumor cells, i.e., tumor cells that have entered the bloodstream, and may be extracted using a suitable separation technique, such as apheresis or conventional venous blood collection. In addition to blood, the body fluid from which the sample is extracted may be urine, gastrointestinal contents or exudate. The term "sample" as used herein also includes situations where e.g. tissue and/or cells and/or body fluids of a subject have been taken from the subject and e.g. have been placed on a microscope slide and a portion of the sample is extracted in order to perform the method, e.g. by Laser Capture Microdissection (LCM) or scraping of cells of interest from the slide, or by fluorescence activated cell sorting techniques. In addition, the term "sample" as used herein also includes situations where, for example, tissue and/or cells and/or bodily fluids of a subject have been removed from the subject and placed on a microscope slide and the method is performed on the slide.

According to another aspect of the invention, an apparatus includes a digital processor configured to perform the inventive method as described herein.

According to another aspect of the invention, a non-transitory storage medium stores instructions executable by a digital processing apparatus to perform the inventive methods as described herein. The non-transitory storage medium may be a computer-readable storage medium, such as a hard disk drive or other magnetic storage medium, an optical disk or other optical storage medium, Random Access Memory (RAM), Read Only Memory (ROM), flash memory or other electronic storage medium, a network server, or the like. The digital processing device may be a handheld device (e.g., a personal data assistant or smart phone), a laptop, a desktop computer, a tablet computer or device, a remote network server, or the like.

According to another aspect of the invention, a computer program comprises program code means for causing a digital processing device to carry out the inventive methods as described herein, when the computer program is run on the digital processing device. The digital processing device may be a handheld device (e.g., a personal data assistant or smart phone), a laptop computer, a desktop computer, a tablet computer or device, a remote network server, or the like.

According to another aspect of the invention, the signal represents a putative activity of the NFkB cellular signaling pathway, wherein the putative activity results from performing the methods of the invention as described herein. The signal may be a digital signal or an analog signal.

According to another aspect of the invention, a kit for measuring the expression level of six or more, e.g. seven, eight, nine, ten, eleven or twelve or more target genes of an NFkB cell signalling pathway in a sample comprises:

polymerase chain reaction primers directed against six or more NFkB target genes,

a probe for six or more NFkB target genes, and

optionally, an apparatus comprising a digital processor configured to perform the inventive methods as described herein, a non-transitory storage medium storing instructions executable by a digital processing apparatus to perform the inventive methods as described herein, or a computer program comprising program code means for causing a digital processing apparatus to perform the inventive methods as described herein when said computer program is run on said digital processing apparatus,

wherein the six or more NFkB target genes are selected from the group consisting of: BCL2L1, BIRC3, CCL2, CCL3, CCL4, CCL5, CCL20, CCL22, CX3CL1, CXCL1, CXCL2, CXCL3, ICAM1, IL1B, IL6, IL8, IRF1, MMP9, NFKB2, NFKBIA, NFKBIE, PTGS2, SELE, STAT5A, TNF, TNFAIP2, TNIP1, TRAF1, and VCAM 1.

Preferably, the first and second electrodes are formed of a metal,

the six or more target genes are selected from the group consisting of: CXCL2, ICAM1, IL6, CCL5, NFKBIA, IL8, TNFAIP2, CXCL3, MMP9, NFKB2, CCL20, CCL2, CXCL1, TNF, IRF1, TRAF1, NFKBIE, VCAM1 and BIRC3, more preferably the six or more target genes comprise three or more, e.g. four, five, six, seven, eight or nine or more target genes selected from the group consisting of: CXCL2, ICAM1, IL6, CCL5, NFKBIA, IL8, TNFAIP2, CXCL3, MMP9, NFKB2, CCL20, CCL2 and CXCL1, most preferably the three or more target genes are selected from the group consisting of: CXCL2, ICAM1, IL6, CCL5, NFKBIA, IL8 and TNFAIP 2.

Preferably, the first and second electrodes are formed of a metal,

the probe comprises at least one of seq.d. nos. 46, 49, 52, 55 and 58 and/or the primer comprises at least one of seq.d. nos. 44 and 45, 47 and 48, 50 and 51, 53 and 54 and 56 and 57.

one or more components for determining the expression level of six or more target genes of the NFkB cellular signaling pathway, and

comprising a digital processor configured to perform the inventive methods as described herein, a non-transitory storage medium storing instructions executable by a digital processing apparatus to perform the inventive methods as described herein, or a computer program comprising program code means for causing a digital processing apparatus to perform the inventive methods as described herein when the computer program is run on the digital processing apparatus,

wherein the one or more components are preferably selected from the group consisting of a microarray chip (e.g., a DNA array chip, an oligonucleotide array chip, a protein array chip), an antibody, a plurality of probes, RNA sequencing, and a set of primers,

wherein the six or more target genes of the NFkB cellular signaling pathway are selected from the group consisting of: BCL2L1, BIRC3, CCL2, CCL3, CCL4, CCL5, CCL20, CCL22, CX3CL1, CXCL1, CXCL2, CXCL3, ICAM1, IL1B, IL6, IL8, IRF1, MMP9, NFKB2, NFKBIA, NFKBIE, PTGS2, SELE, STAT5A, TNF, TNFAIP2, TNIP1, TRAF1, and VCAM 1.

Preferably, the first and second electrodes are formed of a metal,

the six or more target genes are selected from the group consisting of: CXCL2, ICAM1, IL6, CCL5, NFKBIA, IL8, TNFAIP2, CXCL3, MMP9, NFKB2, CCL20, CCL2, CXCL1, TNF, IRF1, TRAF1, NFKBIE, VCAM1 and BIRC3, more preferably said six or more target genes comprise three or more, e.g. four, five, six, seven, eight or nine or more target genes selected from the group consisting of: CXCL2, ICAM1, IL6, CCL5, NFKBIA, IL8, TNFAIP2, CXCL3, MMP9, NFKB2, CCL20, CCL2 and CXCL1, most preferably the three or more target genes are selected from the group consisting of: CXCL2, ICAM1, IL6, CCL5, NFKBIA, IL8, and TNFAIP 2.

By means of such a kit, the expression level of six or more target genes of the NFkB cell signalling pathway can be determined in a simple and comfortable manner. Advantageously, since multiple target genes are used to infer the activity of the NFkB cellular signaling pathway, a more robust inference of the activity of the NFkB cellular signaling pathway can be achieved.

According to another aspect of the invention, a kit of the invention as described herein is used to perform the method of the invention described herein.

The invention described herein may also be used advantageously, for example, in combination with the following objectives:

diagnosing based on the inferred activity of the NFkB cellular signaling pathway;

(ii) performing a prognosis based on the inferred activity of the NFkB cellular signaling pathway;

prescribing a drug based on the inferred activity of the NFkB cellular signaling pathway;

predicting drug efficacy based on the inferred activity of the NFkB cellular signaling pathway;

predicting side effects based on the inferred activity of the NFkB cellular signaling pathway;

monitoring drug efficacy;

developing a drug;

developing an assay;

research of a way;

staging of cancer;

recruitment into clinical trials based on inferred activity of the NFkB cell signaling pathway;

selecting a subsequent test to be performed; and

a companion diagnostic test is selected.

Other advantages will become apparent to those of ordinary skill in the art upon reading and understanding the drawings, the following description and particularly the detailed description provided below.

It shall be understood that the method of claim 1, the device of claim 7, the non-transitory storage medium of claim 8, the computer program of claim 9, the kit of claims 10-14 and the use of the kit of claim 15 have similar and/or identical preferred embodiments, in particular as defined in the dependent claims.

It is to be understood that preferred embodiments of the invention can also be any combination of the dependent claims or the above embodiments with the respective independent claims.

These and other aspects of the invention are apparent from and will be elucidated with reference to the embodiments described hereinafter.

Brief Description of Drawings

FIG. 1 shows schematically and exemplarily the classical and the alternative pathway of NFkB activation (see Dolcet X. et al, "NF-kB in degradation and progression of human cancer", Virchows Archives, Vol.446.No.5,2005, pages 475-482).

Fig. 2 schematically and exemplarily shows a mathematical model, in this case a bayesian network model, for modeling transcription programs of the NFkB cell signaling pathway.

Fig. 3to 6 show the training results of an exemplary bayesian network model based on evidence supported lists (evidence cured list) of target genes of the NFkB cell signaling pathway, 19 target gene candidate lists, 13 target gene candidate lists and 7 target gene candidate lists, respectively (see tables 1 to 4).

Figure 7 shows prediction of NFkB cell signaling pathway activity using an exemplary bayesian network model trained on the list (see table 1) of evidence supporting target genes against diffuse large B-cell lymphoma (DLBCL) samples from GSE 34171.

Figures 8 to 11 show the prediction of NFkB cell signaling pathway activity for an exemplary bayesian network model trained against Normal Human Bronchial Epithelial (NHBE) cell line samples from E-MTAB-1312 stimulated with different TNF α concentrations at different stimulation times using evidence support lists of target genes, 19 target gene candidate lists, 13 target gene candidate lists and 7 target gene candidate lists, respectively (see tables 1 to 4).

Figure 12 shows prediction of NFkB cell signaling pathway activity for THP-1monocytes using an evidence support list of target genes (see table 1), an exemplary bayesian network model trained.

Figures 13 to 16 show the prediction of NFkB cell signaling pathway activity of exemplary bayesian network models trained using the target gene evidence support list, 19 target gene candidate list, 13 target gene candidate list and 7 target gene candidate list, respectively, for colon samples from GSE4183 (see tables 1 to 4).

Figure 17 shows prediction of NFkB cell signaling pathway activity of an exemplary bayesian network model trained against breast cancer cell lines from GSE10890 using an evidence support list of target genes (see table 1).

Figure 18 shows prediction of NFkB cell signaling pathway activity for ovarian samples from GSE20565 using an evidence support list of target genes (see table 1), a trained exemplary bayesian network model.

Figure 19 shows prediction of NFkB cell signaling pathway activity for an exemplary bayesian network model trained against breast cancer samples from E-MTAB-1006 using an evidence support list of target genes (see table 1).

Fig. 20 shows the prognosis of glioma patients (GSE16011) depicted in Kaplan-Meier plots, where a trained exemplary bayesian network model using an evidence support list of target genes (see table 1) was applied.

Fig. 21 shows the training results of an exemplary linear model based on the evidence support list of target genes (see table 1).

Figure 22 shows prediction of NFkB cell signaling pathway activity for an exemplary linear model trained against Normal Human Bronchial Epithelial (NHBE) cell line samples from E-MTAB-1312 stimulated with different TNF α concentrations for different stimulation times, using an evidence-supported list of target genes (see table 1).

Figure 23 shows prediction of NFkB cell signaling pathway activity for colon samples from GSE4183 using evidence support list of target genes (see table 1), an exemplary linear model trained.

Figure 24 shows the training results of an exemplary bayesian network model based on an extensive literature list of putative target genes of the NFkB cellular signaling pathway (see table 5).

Figure 25 shows the prediction of NFkB cell signaling pathway activity for an exemplary bayesian network model trained against a broad literature list of putative target genes of the NFkB cell signaling pathway (see table 5) for Normal Human Bronchial Epithelial (NHBE) cell line samples from E-MTAB-1312 stimulated with different TNF α concentrations for different stimulation times.

Figure 26 shows prediction of NFkB cell signaling pathway activity for colon samples from GSE4183 using an extensive literature list of putative target genes of the NFkB cell signaling pathway (see table 5), an exemplary bayesian network model trained.

Detailed description of the embodiments

The following examples illustrate only particularly preferred methods and selected aspects associated therewith. The teachings provided herein can be used to construct several assays and/or kits, e.g., for detecting, predicting, and/or diagnosing abnormal activity of one or more cellular signaling pathways. Furthermore, when using the methods as described herein, it may be advantageous to guide drug prescription, drug response prediction and drug efficacy (and/or side effect) monitoring may be performed, drug resistance may be predicted and monitored, e.g., selection of subsequent tests to be performed (such as companion diagnostic tests). The following examples should not be construed as limiting the scope of the invention.

Example 1: mathematical model construction

As described in detail in published international patent application WO2013/011479a2 ("association of cellular signaling pathway activity using basic modeling of target gene expression"), by constructing a probabilistic model, such as a bayesian network model, and introducing a conditional probability relationship between the expression level of six or more target genes of a cellular signaling pathway, herein the NFkB cellular signaling pathway, and the level of Transcription Factor (TF) elements, herein the NFkB TF elements, controlling transcription of the six or more target genes of the cellular signaling pathway, such a model can be used to determine the activity of the cellular signaling pathway with high accuracy. Furthermore, the probabilistic model can be easily updated to incorporate additional knowledge gained from later clinical studies, by adjusting conditional probabilities and/or adding new nodes to the model to represent additional information sources. In this way, the probabilistic model can be updated appropriately to embody the latest medical knowledge.

In another readily understandable and interpretable method described in detail in published international patent application WO2013/011479a2 ("association of cellular signaling pathway activity using linear combinations"(s) of target gene expressions "), the activity of a cell signaling pathway-herein an NFkB cell signaling pathway-can be determined by constructing and evaluating a linear or (pseudo) linear model of the relationship between the expression level of six or more target genes incorporating a cell signaling pathway and the level of a Transcription Factor (TF) element-herein an NFkB TF element- (TF element controlling transcription of six or more target genes of a cell signaling pathway), which model is based at least in part on one or more linear combinations of the expression levels of the six or more target genes.

In both methods, the expression level of the six or more target genes may preferably be a measurement of mRNA levels, which may be the result of, for example, (RT) -PCR and microarray techniques using probes related to the target gene mRNA sequences, and RNA sequencing results. In another embodiment, the expression level of the six or more target genes may be measured by protein level, such as the concentration and/or activity of the protein encoded by the target gene.

The above expression levels may optionally be shifted in a number of ways that may or may not be better suited for the application. For example, four different transformations of expression levels, e.g., based on mRNA levels of a microarray, may be:

"continuous data", i.e.expression levels obtained after pretreatment of microarrays with well-known algorithms such as MAS5.0 and fRMA,

"z-fraction", i.e.the continuous expression level proportioned such that the mean value of all samples is 0 and the standard deviation is 1,

"discrete", i.e. each expression above a certain threshold is set to 1 and below to 0 (e.g. the threshold of a probe set may be selected as the mean of the values over a series of several positive and the same number of negative clinical samples),

"fuzzy", i.e. the conversion of successive expression levels into values between 0 and 1 using a sigmoid function of the following formula: 1/(1+ exp ((thr-expr)/se)), where expr is the continuous expression level, thr is a threshold as described above, and se is a softening parameter that affects the difference between 0 and 1.

One of the simplest linear models that can be constructed is a model with nodes representing Transcription Factor (TF) elements-herein NFkB TF elements-in the first layer and weighted nodes representing direct measurements of target gene expression levels, e.g. by one probe set particularly highly correlated to a specific target gene, e.g. in microarray or (q) PCR experiments, in the second layer. The weights may be based on calculations of the training data set or on expert knowledge. This method is particularly simple where multiple expression levels may be measured per target gene (e.g., in microarray experiments where one target gene may be measured with multiple probe sets). A specific way to select one expression level for a particular target gene is to use the expression level in a probe set that best separates the activity of the training data set from the passive sample. One method of identifying such probe sets is to perform a statistical test, such as a t-test, and select the probe set with the lowest p-value. The expression level of the training dataset for the probe set with the lowest p-value is defined as the probe set with the least likelihood of overlap in the expression levels of the (known) active and inactive samples. Another selection method is based on odds ratio. In this model, one or more expression levels are provided for each of the six or more target genes, and the one or more linear combinations comprise linear combinations including a weighted term (weighted term) for each of the six or more target genes, each weighted term being based on only one of the one or more expression levels provided for the respective target gene. If only one expression level is selected for each target gene as described above, this model may be referred to as the "most discriminatory probe set" model.

In an alternative form of the "maximum discrimination probe set" model, where multiple expression levels may be measured for each target gene, all of the expression levels provided by each target gene may be utilized. In this model, one or more expression levels are provided for each of the six or more target genes and the one or more linear combinations include a linear combination of all of the expression levels of the one or more expression levels provided to the six or more target genes. In other words, for each of the six or more target genes, each of the one or more expression levels provided for the respective target gene may be weighted in a linear combination by its own (individual) weight. This variation may be referred to as an "all probe set" model. It has the advantage of being relatively simple and that all provided expression levels can be used.

Both models have in common that they can be considered as "monolayer" models, in which the level of the TF element is calculated based on a linear combination of the expression levels of one or more probe sets of six or more target genes.

After determining the level of a TF element, herein the NFkB TF element, by evaluating the respective model, the determined TF element level can be thresholded to infer the activity of a cell signaling pathway, herein the NFkB cell signaling pathway. A preferred method of calculating such a suitable threshold is by comparing the determined TF element levels wlc of a training sample known to have a passive cell signaling pathway with a training sample having an active cell signaling pathway. The method as such and also taking into account the variance (variance) in these groups is given by using a threshold:

where σ and μ are the standard deviation and mean of the determined TF element level wlc for the training sample. In the case where only a small number of samples are available in the active and/or blunt training samples, then a false count (pseudocount) may be added to the calculated variance based on the average of the variances of the two groups:

where v is the variance of the determined TF element level wlc in the group and x is a positive false count, e.g., 1 or 10, n_actAnd n_pasThe number of active and inactive samples, respectively. The standard deviation σ can be obtained by taking the square root of the variance v.

For ease of explanation, a threshold value may be subtracted from the determined TF element level wlc to obtain a score for the activity of a cellular signaling pathway, where negative values correspond to a passive cellular signaling pathway and positive values correspond to an active cellular signaling pathway.

As an alternative to the "single layer" model described above, a "double layer" model may also be used in embodiments. In this model, a total value ("first (bottom) layer") is calculated for each target gene using linear combination based on the measured intensities of its associated probe sets. The calculated total value is then combined with the total value of other target genes of the cell signaling pathway using further linear combinations ("second (upper)" layer). Likewise, the weights may be known from the training data set or based on expert knowledge or a combination thereof. In other words, in the "bilayer" model, the providing of one or more expression levels and one or more linear combinations for each of the six or more target genes comprises a first linear combination ("first (bottom) layer") of all expression levels of the one or more expression levels provided for the respective target gene for each of the six or more target genes. The model is further based at least in part on additional linear combinations, including a weighted word for each of six or more target genes, each weighted word based on a first linear combination ("second (upper) layer") of the respective target genes.

In a preferred version of the "two-layer" model, the calculation of the total value may include defining a threshold value for each target gene using the training data and subtracting the threshold value from the calculated linear combination to produce the total value for the target gene. The threshold value may be chosen here such that a negative total value of the target gene corresponds to a down-regulated target gene and a positive total value of the target gene corresponds to an up-regulated target gene. The total value of the target gene may also be converted before its combination in the "second (upper) layer" using, for example, one of the above-mentioned conversions (fuzzy, discrete, etc.).

After determining the level of the TF element by evaluating the "double layer" model, the determined TF element level can be thresholded as described above to infer the activity of the cellular signaling pathway.

Hereinafter, the above models are collectively referred to as "(pseudo) linear" models. A more detailed description of the training and use of probabilistic models, such as bayesian network models, is provided in example 3 below.

Example 2: selection of target Gene

Transcription Factors (TFs) are protein complexes (i.e., combinations of proteins held together in a specific structure) or proteins that regulate transcription of a target gene by binding to a specific DNA sequence, thereby controlling transcription of genetic information from DNA to mRNA. The mRNA directly produced as a result of this action of the TF complex is referred to herein as the "direct target gene" (of the transcription factor). Activation of cellular signaling pathways may also lead to more secondary gene transcription, referred to as "indirect target genes". In the following, a (pseudo) linear model or a bayesian network model (as exemplified mathematical model) comprising or consisting of a direct target gene as a direct link between the activity of the cell signaling pathway and the mRNA level is preferred, however, the distinction between direct and indirect target genes is not always obvious. Here, a method of selecting a direct target gene using a scoring function based on available scientific literature data is proposed. Nevertheless, due to limited information and biological variations and uncertainties, accidental selection of indirect target genes cannot be ruled out. To select target genes, two lists of target genes were generated using the MEDLINE database of the National Institute of Health accessible at "www.ncbi.nlm.nih.gov/Pubmed" and further referred to herein as "Pubmed".

Publications containing putative NFkB target genes were searched during the second AND third quarter of 2013 by using queries such as (NFkB AND "target gene"). The resulting publications were further analyzed manually according to the methods described in more detail below.

Specific cellular signaling pathway mRNA target genes are selected from the scientific literature by using a sequencing system, wherein scientific evidence for a specific target gene is evaluated based on the type of scientific experiment in which the evidence accumulates. While some experimental evidence only suggests that the gene is a direct target gene, e.g., mRNA gain is detected by increasing probe set strength on microarrays of cell lines in which the NFkB cell signaling pathway is known to be active, other evidence may be very strong, e.g., the identified NFkB cell signaling pathway TF binding site and the restoration of this site in chromatin immunoprecipitation (ChIP) assays after stimulation of a particular cell signaling pathway in the cell and mRNA gain after specific stimulation of a cell signaling pathway in a cell line.

Several experimental types for the discovery of target genes of specific cell signaling pathways can be identified in the scientific literature:

ChIP assay showing direct binding of TF of the cellular signaling pathway of interest to its binding site on the genome. For example: by using chromatin immunoprecipitation (ChIP) technology, putative functional NFkB TF binding sites in DNA of cell lines with and without induction of activity of the NFkB cell signaling pathway were subsequently identified, e.g. by stimulation with tumor necrosis factor α (TNF α) or Lipopolysaccharide (LPS), as a subset of binding sites recognized based on nucleotide sequences only. Putative functionality was identified as evidence of ChIP derivation and TF was found to bind to the DNA binding site.

2. Electrophoretic Migration Shift (EMSA) assay, which shows in vitro binding of TF to DNA fragments containing binding sequences. The EMSA-based evidence is less strong than the ChIP-based evidence because it cannot be translated into an in vivo situation.

3. Stimulating the cellular signaling pathway and measuring mRNA expression using microarray, RNA sequencing, quantitative PCR or other techniques, using cell lines inducible by the NFkB cellular signaling pathway and measuring the mRNA profile measured at least one but preferably several time points after induction in the presence of cycloheximide that inhibits translation into protein, thus assuming that the induced mRNA is the direct target gene.

4. Similar to 3, but optionally mRNA expression and further subsequent protein abundance measurements, such as Western blots.

5. Bioinformatics methods were used to identify TF binding sites in the genome. For example for NFkB TF elements: using the NFkB binding motif 5'-GGGRNWYYCC-3' (R: A or G, N: any nucleotides, W: A or T, Y: C or T), a software program was run on the human genomic sequence to identify potential binding sites in the gene promoter region and other genomic regions.

6. Similar to 3, only cycloheximide was present.

7. Similar to 4, except that no cycloheximide was present.

In the simplest form, for each of these experimental methods, 1 point can be given to each potential gene, where the gene is identified as a target gene for the NFkB transcription factor family. Using this relative ranking strategy, the most reliable list of target genes can be listed.

Alternatively, sequencing in another way can be used to identify the target gene that is most likely to be the direct target gene by providing a higher number of points by techniques that provide the majority of evidence for the direct target gene in vivo. In the above list, for experimental method 1), this means 8 points, 7 points for method 2), and down to 1 point for experimental method 8). This list may be referred to as a "general list of target genes".

Despite biological variation and uncertainty, the present inventors postulated that the direct target gene is most likely induced in a tissue-independent manner. The list of these target genes may be referred to as an "evidence support list of target genes". The supporting list of evidence for such target genes has been used to construct computational models of the NFkB cell signaling pathway that can be applied to samples from different tissue sources.

As will be exemplified below, how to specifically construct evidence for the NFkB cell signaling pathway supports the selection of a list of target genes.

A scoring function was introduced that provides points for each type of experimental evidence, e.g., ChIP, EMSA, differential expression, knockdown/knock-out, luciferase gene reporter assay, sequence analysis, which has been reported in publications. Sometimes the same experimental evidence is mentioned in multiple publications to obtain a corresponding number of points, e.g. two publications mentioning a ChIP finding results in a double score for a single ChIP finding. Further analysis was performed to allow only genes with different types of experimental evidence, not just one type of experimental evidence, e.g., differential expression. Finally, evidence scores were calculated for all putative NFkB target genes and all putative NFkB target genes with an evidence score of 5 or higher were selected (as shown in table 1). A cutoff level of 5 was chosen heuristically as providing sufficiently strong evidence.

The inventors further selected a supporting list of evidence of target genes (listed in table 1). The evidence of selection supports a list of target genes that proved to be more attentive in determining the activity of NFkB cell signaling pathways from training samples. The selection was made using a combination of literature evidence scores and training results for two different datasets. Three ranks were performed based on evidence score, with the highest rank ranked first, resulting in a lower rank each time one point was decreased, and the "soft" odds ratio for all included probe sets (as shown in table 1) was calculated as described herein using the GSE12195 and E-MTAB-1312 datasets. The absolute value of the Log2 converted "soft" odds ratio was used to rank probe sets; the highest odds ratio ranks first, and so on. As described herein, samples from ABC DLBCL samples from GSE12195 were selected as active NFkB training samples, while normal samples from this dataset were selected as inactive NFkB training samples. In addition, a second set of "soft" odds ratios was calculated using samples from E-MTAB-1312-the optional NFkB training dataset, with control samples used as inactive NFkB samples, and samples stimulated with different concentrations of TNF α for 2 hours selected as active NFkB training samples. A preferred target genome with at least one associated probe set is selected for the "19 target gene candidate list" based on the average rank, which is less than or equal to 20. A more preferred set of target genes with an average ranking of less than or equal to 15 was selected for the "13 target gene candidate list". The most preferred set of target genes with an average ranking of less than or equal to 12 is selected for the "7 target gene candidate list". The 19 target gene candidate lists, 13 target gene candidate lists and 7 target gene candidate lists are shown in tables 2-4, respectively.

Table 1: the "target gene evidence support list" for the NFkB cell signaling pathway in the NFkB cell signaling pathway model and related probe sets for measuring mRNA expression levels of the target gene.

Table 2: "19 target Gene candidate List" of target genes of the NFkB cellular signaling pathway based on literature evidence scores and "Soft" odds ratio for GSE12195 and E-MTAB-1312 "

CXCL2
	ICAM1
IL6
	CCL5
NFKBIA
	IL8
TNFAIP2
	CXCL3
MMP9
	NFKB2
CCL20
	CCL2
CXCL1
	TNF
IRF1
	TRAF1
NFKBIE
	VCAM1
BIRC3

Table 3: "13 target Gene candidate List" of target genes of the NFkB cellular signaling pathway based on literature evidence scores and "Soft" odds ratio for GSE12195 and E-MTAB-1312 "

CXCL2
	ICAM1
IL6
	CCL5
NFKBIA
	IL8
TNFAIP2
	CXCL3
MMP9
	NFKB2
CCL20
	CCL2
CXCL1

Table 4: "7 target gene candidate list" of target genes of the NFkB cell signaling pathway based on literature evidence scores and "soft" odds ratio of GSE12195 and E-MTAB-1312.

Example 3: training and Using mathematical models

Before a mathematical model can be used to infer the activity of a cell signaling pathway, here the NFkB cell signaling pathway, the model must be properly trained.

If the mathematical model is a probabilistic model, such as a bayesian network model, which is based at least in part on conditional probabilities regarding the expression levels of the NFkB TF element and six or more target genes of the NFkB cell signaling pathway measured in the sample, the training may preferably be performed as described in detail in published international patent application WO2013/011479a2 ("association of cellular signaling pathway activity using basic modeling of target gene expression").

If the mathematical model is based at least in part on one or more linear combinations of expression levels of six or more target genes of the NFkB cell signaling pathway measured in the sample, the training may preferably be performed as described in published international patent application WO2014/102668a2 ("association of cellular signaling pathway activity association(s)").

Here, the following figures are used first2, the transcription program of the NFkB cell signalling pathway is modeled in a simple manner. The model consists of three types of nodes: (a) transcription Factor (TF) elements in the first layer 1 (described as "absent" and "present"); (b) second layer 2 target Gene TG₁、TG₂、TG_n(described as "downregulation" and "upregulation"); and (c) a measurement node associated with the expression level of the target gene in the third layer 3. These may be microarray probe sets PS_1,1、PS_1,2、PS_1,3、PS_2,1、PS_n,1、PS _n,m(described as "low" and "high"), as is preferred for use in the present invention, but other gene expression measurements are possible, such as RNAseq or RT-qPCR.

Suitable implementations of the mathematical model, here the exemplary bayesian network model, are based on microarray data. The model describes how (i) the expression level of a target gene depends on the activation of the TF element, and (ii) how the probe set strength in turn depends on the expression level of the respective target gene. For the latter, probe set intensities were obtained from fRMA-pretreated Affymetrix HG-U133Plus2.0 microarrays, which are widely available from Gene Expression Omnibus (GEO, www.ncbi.nlm.nih.gov/GEO) and Arrayexpress (www.ebi.ac.uk/ArrayExpress).

Since the exemplified bayesian network model is a simplification of the biology of the cell signaling pathway, here the NFkB cell signaling pathway, and is generally noisy as a biological measure, a probabilistic approach was chosen, i.e., the relationship between (i) the TF element and the target gene, and (ii) the target gene and its respective probe set, is described in probabilistic terms. Furthermore, it is speculated that the activity of oncogenic cellular signaling pathways driving tumor growth is not transiently and dynamically altered, but rather is chronically or even irreversibly altered. Thus, an example bayesian network model was developed to account for static cell conditions. For this reason, complex dynamic cellular signaling pathway features were not incorporated into the model.

Once the exemplary bayesian network model (see below) is established and calibrated, the model can be used for microarray data for new samples by inputting probe set measurements observed in the third layer 3 and extrapolating back in the model the probabilities necessary for the TF element to "exist". Herein, "presence" is considered to be a phenomenon in which the TF element binds to DNA and controls transcription of a target gene of a cell signaling pathway, and "absence" is a case in which the TF element does not control transcription. Thus, this probability is a raw readout that can be used to represent the activity of a cell signaling pathway, here the NFkB cell signaling pathway, which can then be translated into a probability that the cell signaling pathway is active (i.e., the probability is given by p/(1-p), where p is the probability that the predicted cell signaling pathway is active) by taking the ratio of its probability that it is active over its probability that it is inactive.

In the example Bayesian network model, the probabilistic relationships have been quantified to allow quantitative probabilistic reasoning. To improve the generalization behavior across tissue types, parameters describing the probabilistic relationship between (i) the TF element and the target gene have been carefully chosen. If the TF element is "absent", the target gene is likely to be "down-regulated", so a probability of 0.95 is chosen, and 0.05 is chosen as the probability of the target gene being "up-regulated". The latter (non-zero) probability is a (rare) probability that the target gene is regulated by other factors or is observed "upregulation" (e.g. due to measurement noise) unexpectedly. If the TF element is "present", the target gene is considered to be "up-regulated" with a probability of 0.70 and the target gene is considered to be "down-regulated" with a probability of 0.30. The latter value is chosen because there are some reasons why the target gene is not highly expressed even if the TF element is present, for example because the promoter region of the gene is methylated. In the case where the target gene is not up-regulated by the TF element but down-regulated, the probability is chosen in a similar way, but reflects down-regulation in the presence of the TF element. The parameters describing the relationship between (ii) the target gene and its respective probe set have been calibrated according to experimental data. For the latter, in this example, microarray data from patient samples known to have an active NFkB cell signaling pathway are used, while normal healthy samples from the same dataset are used as inactive NFkB cell signaling pathway samples, but this can also be done using cell line experiments or other patient samples with known states of cell signaling pathway activity. The resulting conditional probability table is given by:

for up-regulated target genes

For down-regulated target genes

In these tables, the variable AL_i,j、AH_i,j、PL_i,jAnd pH_i,jThe number of calibration samples with "absent" (a) or "present" (P) transcription complexes with "low" (L) or "high" (H) probe set intensities, respectively, is indicated. The virtual count is increased to avoid extreme probabilities of 0 and 1.

For discretizing the observed probe set intensities, PS was performed for each probe set_i,jUsing a threshold value t_i,jBelow this threshold the observed value is called "low" and above it is called "high". The threshold is chosen to be the (weighted) median intensity of the probe sets in the calibration dataset used. Due to noise in the microarray data, a fuzzy approach was used when comparing the observed probe set intensities to their threshold values, by assuming a normal distribution with a standard deviation of 0.25 (on a log2 scale) around the reported intensity and determining the probability mass below and above the threshold. The combination of false counts and the use of probabilistic quality instead of deterministic measurements for the calculated odds ratio is referred to herein as a "soft" odds ratio.

Further details regarding the use of mathematical modeling of target gene expression to infer cell signaling pathway activity can be found in Verhaegh W.et al, "Selection of qualified pathway therapy through the use of knowledge-based regulatory models through pathways," Cancer Research, Vol.74, No.11,2014, 2936-.

If instead of the exemplary bayesian network described above, a (pseudo) linear model as described in example 1 above is employed, the weights representing the signs and magnitudes of correlation between the nodes and the threshold values referred to as "absent" or "present" of the nodes need to be determined before the model can be used to infer cell signaling pathway activity in the test sample. Weights and thresholds may be filled out a priori using expert knowledge, but typically the model will be trained using a representative set of training samples, with known training events being preferred, e.g., expression data for probe sets in samples with known "presence" or "absence" of transcription factor complexes (═ inactive cell signaling pathways).

A large number of training algorithms (e.g. regression) are known in the art that take into account the model topology and change the model parameters-here the weights and thresholds, so that the model outputs-here the weighted linear scores-are optimized. Alternatively, the weights can be calculated directly from the observed expression levels without the need for an optimization algorithm.

The first method, referred to herein as the "black and white" method, ends up as a ternary system, where each weight is an element of the set { -1,0,1 }. If placed in a biological context, -1 and 1 correspond to a target gene or probe set, respectively, that is down-regulated and up-regulated in the context of cell signaling pathway activity. If a probe set or target gene does not statistically prove to be up-or down-regulated, it is accepted as having a weight of 0. In one example, both left and right sample t-tests of expression levels of samples with inactive cell signaling pathways may be performed using expression levels of samples with active cell signaling pathways, with the probes or genes being up-or down-regulated in view of the training data used. In the case where the average value of the active samples is statistically greater than the passive samples, i.e., the p-value is below a certain threshold (e.g., 0.3), the target gene or probe set is determined to be up-regulated. Conversely, in the case where the average value of the active sample is statistically lower than that of the passive sample, it is determined that the target gene or probe set is down-regulated upon activation of the cell signaling pathway. In the case where the lowest p-value (left or right) exceeds the above threshold, the weight of the target gene or probe set may be defined as 0.

The second method, referred to as "log probability" -referred to herein as weight-is based on the logarithm of the odds ratio (e.g., base e). The odds ratio for each target gene or probe set is calculated based on the number of positive and negative training samples whose probe set/target gene levels are above and below the respective thresholds (e.g., the (weighted) median of all training samples). False counts may be added to avoid zero as a divisor. A further improvement is to count samples above/below the threshold in a somewhat more probabilistic manner, by assuming that probe set/target gene levels are, for example, normally distributed around their observations with some particular standard deviation (e.g., 0.25 on a2 log scale), and counting the probabilistic masses above and below the threshold.

Here, publicly available data regarding Expression of activated B-cell like (e.g., ABC), diffuse large B-cell lymphoma (DLBCL) cells from known active NFkB cell signaling pathways and normal cells known to have inactive NFkB cell signaling pathways (GSE12195, available from Gene Expression Omnibus (GEO, www.ncbi.nlm.nih.gov/GEO, last visit October 9,2013) are used as examples.

Fig. 3-6 show the training results of an exemplary bayesian network model based on the evidence support list of target genes of the NFkB cellular signaling pathway, 19 target gene candidate lists, 13 target gene candidate lists, and 7 target gene candidate lists (see tables 1-4). In the figure, the vertical axis indicates the probability of TF element "presence" or "absence", which corresponds to the NFkB cell signaling pathway being active or inactive, wherein the values above the horizontal axis correspond to TF element being more likely to be "presence"/active, while values below the horizontal axis indicate that the probability of TF element "absence"/inactive is greater than it is "presence"/active. Group B cells (ABC) known to have activation of an active NFkB cell signaling pathway (group 1) were designated as active NFkB markers, while normal samples comprising known inactive NFkB cell signaling pathways (group 7) were labeled as NFkB inactive. A full score was obtained for the training samples of all four models, which were all ABCs that are active and all normal samples with a passive NFkB cell signaling pathway. As expected, the probability of training the sample becomes less extreme because the model contains fewer target genes. In the same dataset, healthy unstimulated memory B cells and native B cells (groups 5and 6, respectively) were correctly predicted to have a passive NFkB cell signaling pathway in a model of 19 and 7 target genes, with few exceptions. Most other lymphoma samples among germinal center B cells (GCB) (group 4), follicular lymphoma (group 3), lymphoblastoid cell lines (group 2), and diffuse large B-cell lymphoma (DLBCL) samples with unknown subtype (group 8) were predicted to have an active NFkB cell signaling pathway in all four models. For GCB, a high proportion of tumors (> 50%) are known to have Mutations in at least one NFkB regulatory gene, which may be associated with aberrant NFkB activity (see, e.g., Campagno m. et. at, "Mutations of multiple genes use differentiation of NF-kappaB in differential large B-cell lymphoma", Nature, vol.459, No.7247,2009,717 pages 721). Still other studies indicate that constitutive NFkB activation is a common feature of most hematological malignancies (see, e.g., Keutgens A. et al, "defined NF-kB activity in hematological malignancies," Biochemical Pharmacology, Vol.72, No.9,2006, 1069-. (legend: 1-ABC DLBCL; 2-lymphoblastoid cell line; 3-follicular lymphoma; 4-GCB DLBCL; 5-memory B cells; 6-natural B cells; 7-normal; 8-DLBCL unknown subtype)

Hereinafter, the verification results of the trained exemplary bayesian network model using the evidence support list of target genes, the 19 target gene candidate list, the 13 target gene candidate list, and the 7 target gene candidate list, respectively, are shown in fig. 7-19.

Figure 7 shows evidence of target genes using diffuse large B-cell lymphoma (DLBCL) samples from GSE34171 to support prediction of NFkB cell signaling pathway activity for a trained exemplary bayesian network model of the list (see table 1). In the figure, the vertical axis indicates the probability of TF element "presence" or "absence", which corresponds to the NFkB cell signaling pathway being active or inactive, wherein the values above the horizontal axis correspond to TF element being more likely to be "presence"/active, while values below the horizontal axis indicate that the probability of TF element "absence"/inactive is greater than it is "presence"/active. All samples were predicted to have an active NFkB cell signaling pathway. DLBCL lymphomas are known to have NFkB aberrant activity (see, e.g., Keutgens A. et al, "defined NF-kB activity in biological therapeutics), Biochemical Pharmacology, Vol.72, No.9,2006,1069, 1080).

Figures 8-11 show the prediction of NFkB cell signaling pathway activity of an exemplary bayesian network model using the training of evidence support lists of target genes, 19 target gene candidate lists, 13 target gene candidate lists, and 7 target gene candidate lists for Normal Human Bronchial Epithelial (NHBE) cell line samples from E-MTAB-1312 stimulated with different TNF α concentrations for different stimulation times, respectively (see tables 1-4). In the figure, the vertical axis indicates the probability of TF element "presence" or "absence", which corresponds to the NFkB cell signaling pathway being active or inactive, wherein the values above the horizontal axis correspond to TF element being more likely to be "presence"/active, while values below the horizontal axis indicate that the probability of TF element "absence"/inactive is greater than it is "presence"/active. Stimulation of only 0.5h apparently was too short for the NFkB cell Signaling pathway to become active (

groups

5, 9 and 13), while stimulation for more than 4 hours-here 24 hours (

groups

8, 12 and 16) appeared to decrease NFkB cell Signaling pathway activity, as expected due to asynchronous NFkB oscillation, with longer stimulation times resulting in inhibition of net NFkB cell Signaling pathway activity (see, e.g., D.E. Nelson et al, "catalysis in NF-. kappa.B Signaling Control of the Dynamics of Gene Expression", Science, Vol.306, No.5696,2004, page 708). The model using the evidence support list of target genes showed almost complete inhibition of NFkB cell signaling pathway activity in the 24 hour sample, while the model using the 19 target gene candidate list, 13 target gene candidate list and 7 target gene candidate list showed less strong reduction of NFkB cell signaling pathway activity decrease in the 24 hour sample. All control samples without TNF α stimulation (groups 1-4) were correctly predicted to have a passive NFkB cell signaling pathway in all four models. There appears to be no such large difference in cell signaling pathway activity due to increased TNF α concentrations, which is evident in 2 and 4 hour stimulation; it is clear that all concentrations tested in this experiment, even the lowest, are sufficient to have full NFkB cell signalling pathway activity. (legend: 1-no TNF α (0.5 h); 2-no TNF α (2 h); 3-no TNF α (4 h); 4-no TNF α (24 h); 5-low TNF α (0.5 h); 6-low TNF α (2 h); 7-low TNF α (4 h); 8-low TNF α (24 h); 9-medium TNF α (0.5 h); 10-medium TNF α (2 h); 11-medium TNF α (4 h); 12-medium TNF α (24 h); 13-high TNF α (0.5 h); 14-more TNF α (2 h); 15-high TNF α (4 h); 16-high TNF α (24h))

Figure 12 shows prediction of NFkB cell signaling pathway activity using evidence of target genes of THP-1monocytes to support an exemplary bayesian network model trained in the list (see table 1). In the figure, the vertical axis represents the probability of a TF element being "present" or "absent", corresponding to the NFkB cell signaling pathway being active or inactive, wherein values above the horizontal axis correspond to the TF element being more likely to be "present"/active, while values below the horizontal axis indicate that the probability of a TF element being "absent"/inactive is greater than the probability that it is "present"/active. THP-1 cell lines are known to express NFkB cell signaling pathway activity upon stimulation with immune response inducers such as Lipopolysaccharide (LPS). The NFkB cell signaling pathway activity in these monocytes was predicted to be low in the absence of LPS stimulation (group 1). Upon stimulation of these cells with LPS, NFkB cell signaling pathway activity was amplified (group 2). Coenzyme Q10 (coenzyme Q10) has been reported to have anti-inflammatory effects, but the effects on the activity of the NFkB cell signaling pathway have been reported to be limited (see, e.g., c.

"Identification of LPS-insoluble genes downscaled by ubiquitin in human THP-1 cells", Biofactors, Vol.36, No.3,2010, 222-. This is also reflected in NFk predicted in THP-1 cells treated with CoQ10 and stimulated with LPSHigh activity of B cell signaling pathways (group 3). (legend: 1-LPS free; 2-LPS stimulation; 3-LPS stimulation + coenzyme Q10)

Figures 13-16 show the prediction of NFkB cell signaling pathway activity of an exemplary bayesian network model trained using evidence support lists of target genes from a colon sample of GSE4183, 19 target gene candidate lists, 13 target gene candidate lists, and 7 target gene candidate lists (see tables 1-4), respectively. In the figure, the vertical axis indicates the probability of TF element "presence" or "absence", which corresponds to the NFkB cell signaling pathway being active or inactive, wherein the values above the horizontal axis correspond to TF element being more likely to be "presence"/active, while values below the horizontal axis indicate that the probability of TF element "absence"/inactive is greater than it is "presence"/active. By using a model of the target gene support list, most normal samples (group 1) were correctly predicted to have a low probability of NFkB cell signaling pathway activity, however the cell signaling pathway activity of normal samples appeared to be higher than expected for the other data sets in the 19 target gene candidate list, the 13 target gene candidate list, and the 7 target gene candidate list. On the other hand, all four models predict that all Inflammatory Bowel Disease (IBD) (group 2) samples have significantly higher active NFkB cell signaling pathways than normal samples, as expected due to the inflammatory state of the colon in these patients and that the NFkB cell signaling pathways are activated due to inflammation. Furthermore, it is evident from all four models that the NFkB cell signaling pathway is more active in more advanced colorectal cancer (CRC) (group 4) compared to benign adenoma (group 2), possibly due to more mutations as the tumor progresses to a more malignant tumor, inflammation due to the progressing tumor, or leukocyte infiltration due to immune response to late stage cancer. Potentially, the NFkB cell signaling pathway activity score can be used to predict the likelihood of an adenoma progressing to a malignancy. (legend: 1-Normal colon; 2-IBD; 3-adenoma; 4-CRC)

Figure 17 shows prediction of NFkB cell signaling pathway activity using an exemplary bayesian network model trained with an evidence support list of target genes from breast cancer cell lines of GSE10890 (see table 1). In the figure, the vertical axis represents the probability of a TF element being "present" or "absent", corresponding to the NFkB cell signaling pathway being active or inactive, wherein values above the horizontal axis correspond to the TF element being more likely to be "present"/active, while values below the horizontal axis indicate that the probability of a TF element being "absent"/inactive is greater than the probability that it is "present"/active. Some breast cancer cell lines (groups 1 and 2) for which pathways driving cell survival and proliferation are still unknown were identified as having aberrantly active NFkB cell signaling pathways, which may be responsible for cell survival and proliferation. In the third group previously identified as having an active Wnt cell signaling pathway (see published International patent application WO2013/011479A2 "Association of cellular signaling pathway activity using basic modulation of target gene expression"), no NFkB cell signaling pathway active sample was found. (legends: 1 and 2-cell lines driven by unknown cell signaling pathways; 3: cell lines driven by Wnt cell signaling pathways)

Figure 18 shows prediction of NFkB cell signaling pathway activity using an exemplary bayesian network model trained with an evidence support list of target genes from ovarian samples of GSE20565 (see table 1). In the figure, the vertical axis represents the probability of a TF element being "present" or "absent", corresponding to the NFkB cell signaling pathway being active or inactive, wherein values above the horizontal axis correspond to the TF element being more likely to be "present"/active, while values below the horizontal axis indicate that the probability of a TF element being "absent"/inactive is greater than the probability that it is "present"/active. The proportion of samples of predicted NFkB cell signaling pathway activity was significantly higher in primary cancers (groups 1 and 2) compared to breast cancer metastasis to the ovaries (groups 3 and 4), with p ═ 6.0e-5(Fisher exact test). Chronic inflammation is associated with the development and progression of tumors. Recurrent inflammatory processes in the ovary due to ovulation, endometriosis and pelvic infection have been shown to be associated with NFkB cell signaling pathway active tumors (see, e.g., Alvero a.b., "Recent impedances into the role of NF-kappaB in ovarian carcinogenesis", Genome Medicine, vol.2, No.8,2010,56, and Guo r.x.et., incorporated stabilizing for phosphorylated AKT and nuclear factor-kappaB p65and the hair diagnosis with diagnosis in epithelial cancer, Pathology International, Vol.58, No.12,2008, 746. 756). In the ovary, carcinogenesis is associated with inflammatory processes such as repeated ovulation, endometriosis and pelvic infection, possibly resulting in a higher proportion of NFkB cell signalling pathway active tumours originating in the ovary compared to the breast. (legend: 1-Primary ovarian carcinoma; 2-true-like Primary ovarian carcinoma; 3-Breast carcinoma ovarian metastasis; 4-true-like Breast carcinoma ovarian metastasis)

Figure 19 shows prediction of NFkB cell signaling pathway activity using evidence of target genes from breast cancer samples of E-MTAB-1006 to support a trained exemplary bayesian network model of the list (see table 1). In the figure, the vertical axis represents the probability of TF element "presence" or "absence", corresponding to the NFkB cell signaling pathway being active or inactive, wherein values above the horizontal axis correspond to the TF element being more likely to be "present"/active, while values below the horizontal axis indicate that the probability of TF element "absence"/inactive is greater than its probability of "presence"/active. The mean value of the odds ratio of logit NFkB in the inflammatory breast cancer sample (IBC) (group 1) was significantly higher with p <0.01 (dual sample t-test) compared to the non-inflamed breast cancer (nbbc) (group 2). This may be a reflection of the high inflammatory state of IBC compared to nbbc. However, the predicted NFkB cell signaling pathway activities in the two groups overlap to a large extent, making the clear classification of IBC and nbbc based on NFkB cell signaling pathway activities very cumbersome in the current state of the model. (legend: 1-inflammatory Breast cancer; 2-non-inflammatory Breast cancer)

Fig. 20 shows the overall survival of 272 glioma patients (GSE16011) depicted in Kaplan-Meier plots, to which a trained exemplary bayesian network model using an evidence support list of target genes (see table 1) was applied. In the figure, the vertical axis represents the overall survival rate of the patient group and the horizontal axis represents time (expressed in years). The figure shows that the active NFkB TF element (indicated by the steep slope of the curve) is a prognostic marker of poor overall survival. (the patient group with the predicted active NFkB TF element consisted of 113 patients (solid line) and the patient group with the predicted inactive NFkB TF element consisted of 159 patients (dashed line)). The prognostic value of the activity level of the NFkB TF element is also indicated in the risk ratio of the predicted probability of NFkB activity: 1.83 (95% CI: 1.34-2.49, p ═ 7.2 e-5).

Following the exemplary bayesian network model described above, the transcription program of the NFkB cell signaling pathway was modeled in a simple manner using an exemplary linear model. The structure of this model corresponds to the structure shown in FIG. 3 of published International patent application WO2014/1026868A2 ("Association of cellular signalling access utilization(s) of target gene expressions"). More specifically, the exemplified linear model consists of TF nodes, one layer of target gene expression and one layer of mRNA expression levels, and uses continuous expression data, evidence from the target genes to support all target genes in the list (see table 1) and all probe sets included and does not use false counts. Training of this model was performed using the same activity and blunt training samples from GSE12195 and included calculating the target gene expression level-here expressed in probe set strength-the weight of the linkage to the target gene node using the "soft log probability" method as described herein, and then calculating the activity score of the transcription factor complex by multiplying the calculated target gene expression score by the sum of 1 or-1 for up-or down-regulated target genes, respectively.

Fig. 21 shows the training results of an exemplary linear model based on an evidence support list of target genes (see table 1). In this figure, the vertical axis represents the activity score, with positive values corresponding to active NFkB cell signaling pathways and negative values corresponding to inactive NFkB cell signaling pathways. Activated B-cells (ABC) DLBCL (group 1) and normal (group 7) were used as active and blunt training samples, respectively. All training samples were correctly classified; all ABC samples were predicted to have an active NFkB cell signaling pathway, while normal samples were predicted to have a passive NFkB cell signaling pathway. In the same dataset, all but one lymphoma samples and cell lines as well as DLBCL (groups 2-4, 8) were predicted to be NFkB active, similar to the bayesian network model using an evidence-supported list of target genes (figure 3), which seems reasonable in view of the literature evidence described herein. Healthy unstimulated memory B cells and naive B cells (groups 5and 6) were correctly predicted to lack NFkB activity. (legend: 1-ABC DLBCL; 2-lymphoblastoid cell line; 3-follicular lymphoma; 4-GCB DLBCL; 5-memory B cells; 6-natural B cells; 7-normal; 8-DLBCL unknown subtype)

Figure 22 shows prediction of NFkB cell signaling pathway activity using evidence of target genes from Normal Human Bronchial Epithelial (NHBE) cell line samples from E-MTAB-1312 stimulated with different TNF α concentrations at different stimulation times to support an exemplary linear model of training of the list (see table 1). In this figure, the vertical axis represents the activity score, with positive values corresponding to active NFkB cell signaling pathways and negative values corresponding to inactive NFkB cell signaling pathways. The NHBE cell line was either unstimulated or stimulated with different TNF α concentrations for different periods of time. All unstimulated healthy cells (groups 1-4) were correctly predicted to have a passive NFkB cell signaling pathway. Stimulation with all TNF α concentrations for only 0.5h was predicted to be too short for the NFkB cell signaling pathway to become active (

groups

5, 9 and 13), similar to the bayesian network model using evidence-supported lists of target genes (figure 8), while stimulation times of 2-24 hours resulted in active NFkB cell signaling pathways. The reduction in NFkB cell signaling pathway activity after 4 hours observed with the bayesian network model, particularly using the evidence support list of target genes (see fig. 8), cannot be reproduced with the trained exemplary linear model. (legend: 1-no TNF α (0.5 h); 2-no TNF α (2 h); 3-no TNF α (4 h); 4-no TNF α (24 h); 5-low TNF α (0.5 h); 6-low TNF α (2 h); 7-low TNF α (4 h); 8-low TNF α (24 h); 9-medium TNF α (0.5 h); 10-medium TNF α (2 h); 11-medium TNF α (4 h); 12-medium TNF α (24 h); 13-high TNF α (0.5 h); 14-high TNF α (2 h); 15-high TNF α (4 h); 16-high TNF α (24h))

Figure 23 shows prediction of NFkB cell signaling pathway activity using an exemplary linear model trained with an evidence support list (see table 1) of target genes from a colon sample of GSE 4183. In this figure, the vertical axis represents the activity score, with positive values corresponding to active NFkB cell signaling pathways and negative values corresponding to inactive NFkB cell signaling pathways. Most normal samples (group 1) were predicted to have low NFkB cell signaling pathway activity, although the activity score was higher than expected for the other data sets. All inflammatory bowel disease samples (group 2) were predicted to have a higher NFkB activity score than normal samples, and it is reasonable to consider the inflammatory state of the colon (which activates the NFkB cell signalling pathway as one of the inflammatory responses) in these patients. Furthermore, it is clear that samples in the adenoma sample (group 3) are on average lower than the more advanced colorectal cancers (CRC, group 4), which can be partly explained by more mutations resulting from the progression of the tumor to more malignant tumors, inflammation due to tumor progression or leukocyte infiltration due to immune response to late stage cancer. (legend: 1-Normal colon; 2-IBD; 3-adenoma; 4-CRC).

Instead of applying mathematical models, such as the exemplary bayesian network model, to mRNA input data from microarray or RNA sequencing, it may be beneficial to develop specific assays to make sample measurements in clinical applications, such as using qPCR on an integrated platform to determine mRNA levels of target genes. The RNA/DNA sequence of the revealed target gene can then be used to determine which primers and probes are selected on this platform.

Such a dedicated assay can be validated by using a microarray-based mathematical model as a reference model and verifying whether the developed assay provides similar results for a set of validation samples. Following the dedicated assay, similar mathematical models can also be built and calibrated using mRNA sequencing data as input measurements.

Using mathematical models such as the exemplified bayesian network model, microarray/RNA sequencing-based studies, it was found that target genomes that are best representative of the activity of a particular cell signaling pathway can be translated into multiplex quantitative PCR assays performed on samples and/or computers to account for expression measurements and/or to infer the activity of the NFkB cell signaling pathway. To develop such tests for cell signaling pathway activity (e.g., FDA-approved or CLIA-exempt tests in a central service laboratory), it is necessary to develop standardized test kits that require clinical validation in clinical trials for regulatory approval.

The present invention relates to a method comprising inferring activity of an NFkB cellular signaling pathway based at least on measured expression levels of six or more target genes of the NFkB cellular signaling pathway in a sample. The invention also relates to an apparatus comprising a digital processor configured to perform such a method, a non-transitory storage medium storing instructions executable by a digital processing device to perform such a method, and a computer program comprising program code means to cause a digital processing device to perform such a method.

For example, the methods may be used to diagnose (aberrant) activity of the NFkB cell signaling pathway, prognose based on inferred activity of the NFkB cell signaling pathway, recruit clinical trials based on inferred activity of the NFkB cell signaling pathway, select subsequent tests to be performed, select companion diagnostic tests, clinical decision support systems, and the like. In this regard, reference is made to published International patent application WO2013/011479A2 ("Association of cell signaling pathway activity using basic modeling of target gene expression"), published International patent application WO2014/102668A2 ("association of cell signaling pathway activity using(s) of target gene expression") and Verhaegh W.et., "Selection of localized pathway activity pathway use of knowledge modules having specific activity pathway activity, which is incorporated herein by reference, and the detailed description of Cancer pathways, volume Research, 74, 2936, which are incorporated herein by reference.

Example 4: comparison of evidence support lists with broad document lists

A list of target genes of the NFkB cell signaling pathway constructed based on literature evidence according to the procedure described herein (the "target gene evidence support list", see table 1) is compared to a "broad literature list" of putative target genes of the NFkB cell signaling pathway not constructed according to the procedure described above. Another list is due to gene compilation in response to NFkB cell signaling pathway activity provided in Thomson-Reuters' Metecore (final visit time 9/6 days 2013). This database was queried for genes directly transcriptionally regulated downstream of the NFkB protein family, i.e., NFKB1 or p50/p105, NFKB2 or p52/p100, RELA or p65, REL and RELB. This query produced 343 unique genes. Further selections were made based on the number of published references supporting transcriptional regulation of the corresponding genes in the NFkBSMAD family. Genes with ten or more references were selected as broad literature lists. In other words, non-manual management of references and non-experimental evidence-based calculation of evidence scores are performed. This procedure yielded 32 genes, see table 5. Gene expression was measured by 56 probe sets on the Affymetrix HG-u133plus2.0 microarray platform, which were selected using the Bioconductor insert from R and one artificially added DEFB4A probe set, see table 5.

Table 5: an "extensive literature list" of putative target genes for the NFkB cell signaling pathway in the NFkB cell signaling pathway model and related sets of probes for measuring mRNA expression levels of genes.

An exemplary bayesian network model is then constructed using the procedures as described herein. Similar to the description of the NFkB cell signaling pathway model based on the evidence support list, data from fRMA processing of GSE12195 was used to train conditional probability tables for the boundaries between probe sets of this model and their respective putative target genes, including the extensive literature list. The training results are shown in fig. 24. In the figure, the vertical axis indicates the probability of a TF element being "present" or "absent", which corresponds to the NFkB cell signaling pathway being active or inactive, wherein the values above the horizontal axis correspond to the TF element being more likely to be "present"/active, while the values below the horizontal axis indicate that the probability of a TF element being "absent"/inactive is greater than the probability that it is "present"/active. Activated B-cells (ABC) DLBCL (group 1) was used as the active training sample and normal samples (group 7) were used as the inactive training samples. The training results as shown in fig. 24 show the expected clear separation between the passive (group 7) and active (group 1) training samples. In the same dataset, all other lymphoma samples and cell lines as well as DLBCL (groups 2-4, 8) predicted NFkB activity, which is reasonable in view of the literature evidence discussed herein. Healthy unstimulated memory B cells and native B cells (groups 5and 6) were correctly predicted to lack NFkB cell signaling pathway activity. (legend: 1-ABC DLBCL; 2-lymphoblastoid cell line; 3-follicular lymphoma; 4-GCB DLBCL; 5-memory B cells; 6-natural B cells; 7-normal; 8-DLBCL unknown subtype).

Next, an exemplary network bayesian model based on extensive literature list training was tested on many datasets.

Figure 25 shows the prediction of NFkB cell signaling pathway activity for an exemplary bayesian network model trained using an extensive literature list of putative target genes of the NFkB cell signaling pathway (see table 5) for Normal Human Bronchial Epithelial (NHBE) cell line samples from E-MTAB-1312 stimulated with different TNF α concentrations for different stimulation times. In the figure, the vertical axis indicates the probability of a TF element being "present" or "absent", which corresponds to the NFkB cell signaling pathway being active or inactive, wherein the values above the horizontal axis correspond to the TF element being more likely to be "present"/active, and the values below the horizontal axis indicate that the probability of a TF element being "absent"/inactive is greater than the probability that it is "present"/active. All unstimulated healthy cells were correctly predicted to have a passive NFkB cell signaling pathway up to 24 hours (groups 1-3). Absence of stimulation for 24 hours results in the predicted accidental activation of the NFkB cell signaling pathway. Extensive literature bayesian models predict that stimulation with all TNF α concentrations for only 0.5h is also too short for the NFkB cell signaling pathway to become active (

groups

5, 9 and 13), while stimulation times of 2-24 hours result in active NFkB cell signaling pathways (groups 5-8, 9-12 and 13-15). The evidence support list using target genes (see figure 8) was not reproduced using the trained extensive literature bayesian network model and a reduction in NFkB cell signaling pathway activity after 4 hours was observed with the bayesian network model. (legend: 1-no TNF α (0.5 h); 2-no TNF α (2 h); 3-no TNF α (4 h); 4-no TNF α (24 h); 5-low TNF α (0.5 h); 6-low TNF α (2 h); 7-low TNF α (4 h); 8-low TNF α (24 h); 9-medium TNF α (0.5 h); 10-medium TNF α (2 h); 11-medium TNF α (4 h); 12-medium TNF α (24 h); 13-high TNF α (0.5 h); 14-high TNF α (2 h); 15-high TNF α (4 h); 16-high TNF α (24h))

Figure 26 shows prediction of NFkB cell signaling pathway activity using an extensive literature list of putative target genes of the NFkB cell signaling pathway (see table 5), an exemplary bayesian network model of training of colon samples from GSE 4183. In the figure, the vertical axis represents the probability of TF element being "present" or "absent", corresponding to the NFkB cell signaling pathway being active or inactive, wherein the values above the horizontal axis correspond to the TF element being more likely to be "present"/active, while the values below the horizontal axis indicate that the probability of TF element being "absent"/inactive is greater than the probability that it is "present"/active. All adenoma samples except one were predicted to have an active NFkB cell signaling pathway by extensive literature bayesian network models, which is particularly undesirable in normal healthy colon samples (group 1). (legend: 1-Normal colon; 2-IBD; 3-adenoma; 4-CRC)

Example 5: primers and probes for use in kits

Preferred PCR primers and probes for use in the kit are listed in Table 6 below. The PCR primers For each gene are called forward (For) and reverse (Rev) primers, and the probes used to detect the PCR product For each gene are labeled probes. In one non-limiting embodiment, the probes listed in Table 6 are labeled with a 5'FAM dye with an internal ZEN Quencher and 3' Iowa Black Fluorescent Quencher (IBFQ).

Table 6: non-limiting examples of primers and probes for a kit for measuring gene expression of NFkB target genes

Preferably, the first and second electrodes are formed of a metal,

the kit comprises one or more components for measuring the expression level of a control gene, wherein the one or more components comprise PCR primers and probes for at least one control gene listed in table 7. The PCR primers for each gene are referred to as forward (F) and reverse (R) primers, and the probes used to detect the PCR product for each gene are labeled probes (P or FAM). In one non-limiting embodiment, the probes listed in Table 7 are labeled with a 5'FAM dye with an internal ZEN Quencher and 3' Iowa Black Fluorescent Quencher (IBFQ).

Table 7: oligonucleotide sequences for control

A sequence table:

seq. No. Gene:

Seq.1 BCL2

Seq.2 BCL2L1

Seq.3 BIRC3

Seq.4 CCL2

Seq.5 CCL3

Seq.6 CCL4

Seq.7 CCL5

Seq.8 CCL20

Seq.9 CCL22

Seq.10 CSF2

Seq.11 CX3CL1

Seq.12 CXCL1

Seq.13 CXCL2

Seq.14 CXCL3

Seq.15 CXCL10

Seq.16 DEFB4A

Seq.17 FASLG

Seq.18 GCLC

Seq.19 ICAM1

Seq.20 IER3

Seq.21 IFNB1

Seq.22 IL12B

Seq.23 IL1B

Seq.24 IL2

Seq.25 IL23A

Seq.26 IL6

Seq.27 IL8

Seq.28 IRF1

Seq.29 MMP9

Seq.30 MYC

Seq.31 NFKB2

Seq.32 NFKBIA

Seq.33 NFKBIE

Seq.34 NOS2

Seq.35 PTGS2

Seq.36 SELE

Seq.37 SOD2

Seq.38 STAT5A

Seq.39 TNF

Seq.40 TNFAIP2

Seq.41 TNIP1

Seq.42 TRAF1

Seq.43 VCAM1

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tgcagtatgc tccacgtggt aagatcctcc aagctgcttt agaagtaaca atgaagaacg 3840

tggacgtttt taatataaag cctgttttgt cttttgttgt tgttcaaacg ggattcacag 3900

agtatttgaa aaatgtatat atattaagag gtcacggggg ctaattgctg gctggctgcc 3960

ttttgctgtg gggttttgtt acctggtttt aataacagta aatgtgccca gcctcttggc 4020

cccagaactg tacagtattg tggctgcact tgctctaaga gtagttgatg ttgcattttc 4080

cttattgtta aaaacatgtt agaagcaatg aatgtatata aaagcctcaa ctagtcattt 4140

ttttctcctc ttcttttttt tcattatatc taattatttt gcagttgggc aacagagaac 4200

catccctatt ttgtattgaa gagggattca catctgcatc ttaactgctc tttatgaatg 4260

aaaaaacagt cctctgtatg tactcctctt tacactggcc agggtcagag ttaaatagag 4320

tatatgcact ttccaaattg gggacaaggg ctctaaaaaa agccccaaaa ggagaagaac 4380

atctgagaac ctcctcggcc ctcccagtcc ctcgctgcac aaatactccg caagagaggc 4440

cagaatgaca gctgacaggg tctatggcca tcgggtcgtc tccgaagatt tggcaggggc 4500

agaaaactct ggcaggctta agatttggaa taaagtcaca gaattaagga agcacctcaa 4560

tttagttcaa acaagacgcc aacattctct ccacagctca cttacctctc tgtgttcaga 4620

tgtggccttc catttatatg tgatctttgt tttattagta aatgcttatc atctaaagat 4680

gtagctctgg cccagtggga aaaattagga agtgattata aatcgagagg agttataata 4740

atcaagatta aatgtaaata atcagggcaa tcccaacaca tgtctagctt tcacctccag 4800

gatctattga gtgaacagaa ttgcaaatag tctctatttg taattgaact tatcctaaaa 4860

caaatagttt ataaatgtga acttaaactc taattaattc caactgtact tttaaggcag 4920

tggctgtttt tagactttct tatcacttat agttagtaat gtacacctac tctatcagag 4980

aaaaacagga aaggctcgaa atacaagcca ttctaaggaa attagggagt cagttgaaat 5040

tctattctga tcttattctg tggtgtcttt tgcagcccag acaaatgtgg ttacacactt 5100

tttaagaaat acaattctac attgtcaagc ttatgaaggt tccaatcaga tctttattgt 5160

tattcaattt ggatctttca gggatttttt ttttaaatta ttatgggaca aaggacattt 5220

gttggagggg tgggagggag gaagaatttt taaatgtaaa acattcccaa gtttggatca 5280

gggagttgga agttttcaga ataaccagaa ctaagggtat gaaggacctg tattggggtc 5340

gatgtgatgc ctctgcgaag aaccttgtgt gacaaatgag aaacattttg aagtttgtgg 5400

tacgaccttt agattccaga gacatcagca tggctcaaag tgcagctccg tttggcagtg 5460

caatggtata aatttcaagc tggatatgtc taatgggtat ttaaacaata aatgtgcagt 5520

tttaactaac aggatattta atgacaacct tctggttggt agggacatct gtttctaaat 5580

gtttattatg tacaatacag aaaaaaattt tataaaatta agcaatgtga aactgaattg 5640

gagagtgata atacaagtcc tttagtctta cccagtgaat cattctgttc catgtctttg 5700

gacaaccatg accttggaca atcatgaaat atgcatctca ctggatgcaa agaaaatcag 5760

atggagcatg aatggtactg taccggttca tctggactgc cccagaaaaa taacttcaag 5820

caaacatcct atcaacaaca aggttgttct gcataccaag ctgagcacag aagatgggaa 5880

cactggtgga ggatggaaag gctcgctcaa tcaagaaaat tctgagacta ttaataaata 5940

agactgtagt gtagatactg agtaaatcca tgcacctaaa ccttttggaa aatctgccgt 6000

gggccctcca gatagctcat ttcattaagt ttttccctcc aaggtagaat ttgcaagagt 6060

gacagtggat tgcatttctt ttggggaagc tttcttttgg tggttttgtt tattatacct 6120

tcttaagttt tcaaccaagg tttgcttttg ttttgagtta ctggggttat ttttgtttta 6180

aataaaaata agtgtacaat aagtgttttt gtattgaaag cttttgttat caagattttc 6240

atacttttac cttccatggc tctttttaag attgatactt ttaagaggtg gctgatattc 6300

tgcaacactg tacacataaa aaatacggta aggatacttt acatggttaa ggtaaagtaa 6360

gtctccagtt ggccaccatt agctataatg gcactttgtt tgtgttgttg gaaaaagtca 6420

cattgccatt aaactttcct tgtctgtcta gttaatattg tgaagaaaaa taaagtacag 6480

tgtgagatac tg 6492

<210> 2

<211> 2575

<212> DNA

<213> Homo sapiens

<400> 2

ggaggaggaa gcaagcgagg gggctggttc ctgagcttcg caattcctgt gtcgccttct 60

gggctcccag cctgccgggt cgcatgatcc ctccggccgg agctggtttt tttgccagcc 120

accgcgaggc cggctgagtt accggcatcc ccgcagccac ctcctctccc gacctgtgat 180

acaaaagatc ttccgggggc tgcacctgcc tgcctttgcc taaggcggat ttgaatctct 240

ttctctccct tcagaatctt atcttggctt tggatcttag aagagaatca ctaaccagag 300

acgagactca gtgagtgagc aggtgttttg gacaatggac tggttgagcc catccctatt 360

ataaaaatgt ctcagagcaa ccgggagctg gtggttgact ttctctccta caagctttcc 420

cagaaaggat acagctggag tcagtttagt gatgtggaag agaacaggac tgaggcccca 480

gaagggactg aatcggagat ggagaccccc agtgccatca atggcaaccc atcctggcac 540

ctggcagaca gccccgcggt gaatggagcc actggccaca gcagcagttt ggatgcccgg 600

gaggtgatcc ccatggcagc agtaaagcaa gcgctgaggg aggcaggcga cgagtttgaa 660

ctgcggtacc ggcgggcatt cagtgacctg acatcccagc tccacatcac cccagggaca 720

gcatatcaga gctttgaaca ggtagtgaat gaactcttcc gggatggggt aaactggggt 780

cgcattgtgg cctttttctc cttcggcggg gcactgtgcg tggaaagcgt agacaaggag 840

atgcaggtat tggtgagtcg gatcgcagct tggatggcca cttacctgaa tgaccaccta 900

gagccttgga tccaggagaa cggcggctgg gatacttttg tggaactcta tgggaacaat 960

gcagcagccg agagccgaaa gggccaggaa cgcttcaacc gctggttcct gacgggcatg 1020

actgtggccg gcgtggttct gctgggctca ctcttcagtc ggaaatgacc agacactgac 1080

catccactct accctcccac ccccttctct gctccaccac atcctccgtc cagccgccat 1140

tgccaccagg agaaccacta catgcagccc atgcccacct gcccatcaca gggttgggcc 1200

cagatctggt cccttgcagc tagttttcta gaatttatca cacttctgtg agacccccac 1260

acctcagttc ccttggcctc agaattcaca aaatttccac aaaatctgtc caaaggaggc 1320

tggcaggtat ggaagggttt gtggctgggg gcaggagggc cctacctgat tggtgcaacc 1380

cttacccctt agcctccctg aaaatgtttt tctgccaggg agcttgaaag ttttcagaac 1440

ctcttcccca gaaaggagac tagattgcct ttgttttgat gtttgtggcc tcagaattga 1500

tcattttccc cccactctcc ccacactaac ctgggttccc tttccttcca tccctacccc 1560

ctaagagcca tttaggggcc acttttgact agggattcag gctgcttggg ataaagatgc 1620

aaggaccagg actccctcct cacctctgga ctggctagag tcctcactcc cagtccaaat 1680

gtcctccaga agcctctggc tagaggccag ccccacccag gagggagggg gctatagcta 1740

caggaagcac cccatgccaa agctagggtg gcccttgcag ttcagcacca ccctagtccc 1800

ttcccctccc tggctcccat gaccatactg agggaccaac tgggcccaag acagatgccc 1860

cagagctgtt tatggcctca gctgcctcac ttcctacaag agcagcctgt ggcatctttg 1920

ccttgggctg ctcctcatgg tgggttcagg ggactcagcc ctgaggtgaa agggagctat 1980

caggaacagc tatgggagcc ccagggtctt ccctacctca ggcaggaagg gcaggaagga 2040

gagcctgctg catggggtgg ggtagggctg actagaaggg ccagtcctgc ctggccaggc 2100

agatctgtgc cccatgcctg tccagcctgg gcagccaggc tgccaaggcc agagtggcct 2160

ggccaggagc tcttcaggcc tccctctctc ttctgctcca cccttggcct gtctcatccc 2220

caggggtccc agccaccccg ggctctctgc tgtacatatt tgagactagt ttttattcct 2280

tgtgaagatg atatactatt tttgttaagc gtgtctgtat ttatgtgtga ggagctgctg 2340

gcttgcagtg cgcgtgcacg tggagagctg gtgcccggag attggacggc ctgatgctcc 2400

ctcccctgcc ctggtccagg gaagctggcc gagggtcctg gctcctgagg ggcatctgcc 2460

cctcccccaa cccccacccc acacttgttc cagctctttg aaatagtctg tgtgaaggtg 2520

aaagtgcagt tcagtaataa actgtgttta ctcagtgaaa aaaaaaaaaa aaaaa 2575

<210> 3

<211> 6932

<212> DNA

<213> Homo sapiens

<400> 3

gcatttaaaa gacagcgtga gactcgcgcc ctccggcacg gaaaaggcca ggcgacaggt 60

gtcgcttgaa aagactgggc ttgtccttgc tggtgcatgc gtcgtcggcc tctgggcagc 120

aggtttacaa aggaggaaaa cgacttcttc tagatttttt tttcagtttc ttctataaat 180

caaaacatct caaaatggag acctaaaatc cttaaaggga cttagtctaa tctcgggagg 240

tagttttgtg catgggtaaa caaattaagt attaactggt gttttactat ccaaagaatg 300

ctaattttat aaacatgatc gagttatata aggtatacca taatgagttt gattttgaat 360

ttgatttgtg gaaataaagg aaaagtgatt ctagctgggg catattgtta aagcattttt 420

ttcagagttg gccaggcagt ctcctactgg cacattctcc cattatgtag aatagaaata 480

gtacctgtgt ttgggaaaga ttttaaaatg agtgacagtt atttggaaca aagagctaat 540

aatcaatcca ctgcaaatta aagaaacatg cagatgaaag ttttgacaca ttaaaatact 600

tctacagtga caaagaaaaa tcaagaacaa agctttttga tatgtgcaac aaatttagag 660

gaagtaaaaa gataaatgtg atgattggtc aagaaattat ccagttattt acaaggccac 720

tgatatttta aacgtccaaa agtttgttta aatgggctgt taccgctgag aatgatgagg 780

atgagaatga tggttgaagg ttacatttta ggaaatgaag aaacttagaa aattaatata 840

aagacagtga tgaatacaaa gaagattttt ataacaatgt gtaaaatttt tggccaggga 900

aaggaatatt gaagttagat acaattactt acctttgagg gaaataattg ttggtaatga 960

gatgtgatgt ttctcctgcc acctggaaac aaagcattga agtctgcagt tgaaaagccc 1020

aacgtctgtg agatccagga aaccatgctt gcaaaccact ggtaaaaaaa aaaaaaaaaa 1080

aaaaaaaaag ccacagtgac ttgcttattg gtcattgcta gtattatcga ctcagaacct 1140

ctttactaat ggctagtaaa tcataattga gaaattctga attttgacaa ggtctctgct 1200

gttgaaatgg taaatttatt attttttttg tcatgataaa ttctggttca aggtatgcta 1260

tccatgaaat aatttctgac caaaactaaa ttgatgcaat ttgattatcc atcttagcct 1320

acagatggca tctggtaact tttgactgtt ttaaaaaata aatccactat cagagtagat 1380

ttgatgttgg cttcagaaac atttagaaaa acaaaagttc aaaaatgttt tcaggaggtg 1440

ataagttgaa taactctaca atgttagttc tttgaggggg acaaaaaatt taaaatcttt 1500

gaaaggtctt attttacagc catatctaaa ttatcttaag aaaattttta acaaagggaa 1560

tgaaatatat atcatgattc tgtttttcca aaagtaacct gaatatagca atgaagttca 1620

gttttgttat tggtagtttg ggcagagtct ctttttgcag cacctgttgt ctaccataat 1680

tacagaggac atttccatgt tctagccaag tatactatta gaataaaaaa acttaacatt 1740

gagttgcttc aacagcatga aactgagtcc aaaagaccaa atgaacaaac acattaatct 1800

ctgattattt attttaaata gaatatttaa ttgtgtaaga tctaatagta tcattatact 1860

taagcaatca tattcctgat gatctatggg aaataactat tatttaatta atattgaaac 1920

caggttttaa gatgtgttag ccagtcctgt tactagtaaa tctctttatt tggagagaaa 1980

ttttagattg ttttgttctc cttattagaa ggattgtaga aagaaaaaaa tgactaattg 2040

gagaaaaatt ggggatatat catatttcac tgaattcaaa atgtcttcag ttgtaaatct 2100

taccattatt ttacgtacct ctaagaaata aaagtgcttc taattaaaat atgatgtcat 2160

taattatgaa atacttcttg ataacagaag ttttaaaata gccatcttag aatcagtgaa 2220

atatggtaat gtattatttt cctcctttga gttaggtctt gtgctttttt ttcctggcca 2280

ctaaatttca caatttccaa aaagcaaaat aaacatattc tgaatatttt tgctgtgaaa 2340

cacttgacag cagagctttc caccatgaaa agaagcttca tgagtcacac attacatctt 2400

tgggttgatt gaatgccact gaaacattct agtagcctgg agaagttgac ctacctgtgg 2460

agatgcctgc cattaaatgg catcctgatg gcttaataca catcactctt ctgtgaaggg 2520

ttttaatttt caacacagct tactctgtag catcatgttt acattgtatg tataaagatt 2580

atacaaaggt gcaattgtgt atttcttcct taaaatgtat cagtatagga tttagaatct 2640

ccatgttgaa actctaaatg catagaaata aaaataataa aaaatttttc attttggctt 2700

ttcagcctag tattaaaact gataaaagca aagccatgca caaaactacc tccctagaga 2760

aaggctagtc ccttttcttc cccattcatt tcattatgaa catagtagaa aacagcatat 2820

tcttatcaaa tttgatgaaa agcgccaaca cgtttgaact gaaatacgac ttgtcatgtg 2880

aactgtaccg aatgtctacg tattccactt ttcctgctgg ggttcctgtc tcagaaagga 2940

gtcttgctcg tgctggtttc tattacactg gtgtgaatga caaggtcaaa tgcttctgtt 3000

gtggcctgat gctggataac tggaaaagag gagacagtcc tactgaaaag cataaaaagt 3060

tgtatcctag ctgcagattc gttcagagtc taaattccgt taacaacttg gaagctacct 3120

ctcagcctac ttttccttct tcagtaacaa attccacaca ctcattactt ccgggtacag 3180

aaaacagtgg atatttccgt ggctcttatt caaactctcc atcaaatcct gtaaactcca 3240

gagcaaatca agatttttct gccttgatga gaagttccta ccactgtgca atgaataacg 3300

aaaatgccag attacttact tttcagacat ggccattgac ttttctgtcg ccaacagatc 3360

tggcaaaagc aggcttttac tacataggac ctggagacag agtggcttgc tttgcctgtg 3420

gtggaaaatt gagcaattgg gaaccgaagg ataatgctat gtcagaacac ctgagacatt 3480

ttcccaaatg cccatttata gaaaatcagc ttcaagacac ttcaagatac acagtttcta 3540

atctgagcat gcagacacat gcagcccgct ttaaaacatt ctttaactgg ccctctagtg 3600

ttctagttaa tcctgagcag cttgcaagtg cgggttttta ttatgtgggt aacagtgatg 3660

atgtcaaatg cttttgctgt gatggtggac tcaggtgttg ggaatctgga gatgatccat 3720

gggttcaaca tgccaagtgg tttccaaggt gtgagtactt gataagaatt aaaggacagg 3780

agttcatccg tcaagttcaa gccagttacc ctcatctact tgaacagctg ctatccacat 3840

cagacagccc aggagatgaa aatgcagagt catcaattat ccattttgaa cctggagaag 3900

accattcaga agatgcaatc atgatgaata ctcctgtgat taatgctgcc gtggaaatgg 3960

gctttagtag aagcctggta aaacagacag ttcagagaaa aatcctagca actggagaga 4020

attatagact agtcaatgat cttgtgttag acttactcaa tgcagaagat gaaataaggg 4080

aagaggagag agaaagagca actgaggaaa aagaatcaaa tgatttatta ttaatccgga 4140

agaatagaat ggcacttttt caacatttga cttgtgtaat tccaatcctg gatagtctac 4200

taactgccgg aattattaat gaacaagaac atgatgttat taaacagaag acacagacgt 4260

ctttacaagc aagagaactg attgatacga ttttagtaaa aggaaatatt gcagccactg 4320

tattcagaaa ctctctgcaa gaagctgaag ctgtgttata tgagcattta tttgtgcaac 4380

aggacataaa atatattccc acagaagatg tttcagatct accagtggaa gaacaattgc 4440

ggagactaca agaagaaaga acatgtaaag tgtgtatgga caaagaagtg tccatagtgt 4500

ttattccttg tggtcatcta gtagtatgca aagattgtgc tccttcttta agaaagtgtc 4560

ctatttgtag gagtacaatc aagggtacag ttcgtacatt tctttcatga agaagaacca 4620

aaacatcgtc taaactttag aattaattta ttaaatgtat tataacttta acttttatcc 4680

taatttggtt tccttaaaat ttttatttat ttacaactca aaaaacattg ttttgtgtaa 4740

catatttata tatgtatcta aaccatatga acatatattt tttagaaact aagagaatga 4800

taggcttttg ttcttatgaa cgaaaaagag gtagcactac aaacacaata ttcaatcaaa 4860

atttcagcat tattgaaatt gtaagtgaag taaaacttaa gatatttgag ttaaccttta 4920

agaattttaa atattttggc attgtactaa taccgggaac atgaagccag gtgtggtggt 4980

atgtgcctgt agtcccaggc tgaggcaaga gaattacttg agcccaggag tttgaatcca 5040

tcctgggcag catactgaga ccctgccttt aaaaacaaac agaacaaaaa caaaacacca 5100

gggacacatt tctctgtctt ttttgatcag tgtcctatac atcgaaggtg tgcatatatg 5160

ttgaatgaca ttttagggac atggtgtttt tataaagaat tctgtgagaa aaaatttaat 5220

aaagcaacaa aaattactct tattcttcat tgctttattt caatgacatt ggatagttta 5280

gtcactccca gactctttcc ataccttctt aaagcctctc aaatattgaa ctacagttta 5340

tactccttcc cataagatgc ttcttcattg acacttgtag aacacggggt caacacatca 5400

taaaatctat tatggaatgc ctgagacaag aatcaaacag tccctttagt aagtttgttt 5460

attcacttct ctattgattc attcaagaag tctcatgcca gccccaccta ttggaagaag 5520

gtctgagttt tattcttatc tctttggtat taattctgaa acttagaaag tacactggtt 5580

agcaatgctt gggaccaaca ggttgttctg gtaaataaat ctgtttcata ttgtcagtgc 5640

aacaaaatgt ccccctctgc attatgttat tggtactcaa cacgtccgag tcataactct 5700

gtcctttgct tcttatagag gtattaggtc ttcaagagca gaagtaagac tgtaataggg 5760

aatactcagg ggaaggcagg caaaggctag tcatctaaac cagttctaga tgtctgtata 5820

ggggcagatg gctctgtaag ggcagaaggg aaagacccct tcataagggt cacagctgac 5880

aatcctataa caaaagacag gttaacaaga gaaaaactta acaaatttat ttaatcacag 5940

atttacatca ccggggagcc ttcgtaatga agatccaaaa ttacagggga aactgtgcat 6000

ttttatgctt aggtttgata atgaatggac agccctgaag aatagtgatt ggaaaaaaag 6060

gatatgatct aatgggaata gacacaggtt ggggacccag caaggcctgt ctgttcagat 6120

tattcttggt ctctgtgcag cattccttcc tcctggatat agggcagggc ctgtatggga 6180

tggggatatt ataacctgct atcaagcaag gtaggtcaga gaatttattt atggccagct 6240

cttacatagt taggtgagga aagattagag tactatcttt aagatgtaag tctggcattg 6300

tggaaagatg gttccagttt ctatgaccta ccttggggaa gaggaattca agtttctgtg 6360

gcttgccttc agggagaatg aggctgagac aggagggcag gataacatca gagaaaaact 6420

ttgcttctga ggccttcact ttgggttttc tgagccccaa catctgctag tgttgtaaag 6480

agaacaatta gggaccaagt gaggggagga aagaatccat ctctgcattc tgatgctggg 6540

agacttattt ccttgaaatg caattgattt tgcctctgct aagaggctct gctggctacc 6600

catgtactag ccagtgtcct gcatgggtgc taggctgaat tatttgtaat tgtgcttagg 6660

tgatttgtaa ctcaggtata gggtatttaa atagtaggca ccctttttgc accatgtgtt 6720

ttttttttta tctagttctt gtatactaca gataatattt gaactttgtc atctcactgt 6780

aaaacttttg ttcatttctc attatggtaa taaatagcta ttataaccaa cccatttatt 6840

caaatatgtt atttccctaa gtgttatttt gacattttgt tttggaaaaa ataaatcacc 6900

atagataata aaaaaaaaaa aaaaaaaaaa aa 6932

<210> 4

<211> 760

<212> DNA

<213> Homo sapiens

<400> 4

gaggaaccga gaggctgaga ctaacccaga aacatccaat tctcaaactg aagctcgcac 60

tctcgcctcc agcatgaaag tctctgccgc ccttctgtgc ctgctgctca tagcagccac 120

cttcattccc caagggctcg ctcagccaga tgcaatcaat gccccagtca cctgctgtta 180

taacttcacc aataggaaga tctcagtgca gaggctcgcg agctatagaa gaatcaccag 240

cagcaagtgt cccaaagaag ctgtgatctt caagaccatt gtggccaagg agatctgtgc 300

tgaccccaag cagaagtggg ttcaggattc catggaccac ctggacaagc aaacccaaac 360

tccgaagact tgaacactca ctccacaacc caagaatctg cagctaactt attttcccct 420

agctttcccc agacaccctg ttttatttta ttataatgaa ttttgtttgt tgatgtgaaa 480

cattatgcct taagtaatgt taattcttat ttaagttatt gatgttttaa gtttatcttt 540

catggtacta gtgtttttta gatacagaga cttggggaaa ttgcttttcc tcttgaacca 600

cagttctacc cctgggatgt tttgagggtc tttgcaagaa tcattaatac aaagaatttt 660

ttttaacatt ccaatgcatt gctaaaatat tattgtggaa atgaatattt tgtaactatt 720

acaccaaata aatatatttt tgtacaaaaa aaaaaaaaaa 760

<210> 5

<211> 813

<212> DNA

<213> Homo sapiens

<400> 5

agctggtttc agacttcaga aggacacggg cagcagacag tggtcagtcc tttcttggct 60

ctgctgacac tcgagcccac attccgtcac ctgctcagaa tcatgcaggt ctccactgct 120

gcccttgctg tcctcctctg caccatggct ctctgcaacc agttctctgc atcacttgct 180

gctgacacgc cgaccgcctg ctgcttcagc tacacctccc ggcagattcc acagaatttc 240

atagctgact actttgagac gagcagccag tgctccaagc ccggtgtcat cttcctaacc 300

aagcgaagcc ggcaggtctg tgctgacccc agtgaggagt gggtccagaa atatgtcagc 360

gacctggagc tgagtgcctg aggggtccag aagcttcgag gcccagcgac ctcggtgggc 420

ccagtgggga ggagcaggag cctgagcctt gggaacatgc gtgtgacctc cacagctacc 480

tcttctatgg actggttgtt gccaaacagc cacactgtgg gactcttctt aacttaaatt 540

ttaatttatt tatactattt agtttttgta atttattttc gatttcacag tgtgtttgtg 600

attgtttgct ctgagagttc ccctgtcccc tcccccttcc ctcacaccgc gtctggtgac 660

aaccgagtgg ctgtcatcag cctgtgtagg cagtcatggc accaaagcca ccagactgac 720

aaatgtgtat cggatgcttt tgttcagggc tgtgatcggc ctggggaaat aataaagatg 780

ctcttttaaa aggtaaaaaa aaaaaaaaaa aaa 813

<210> 6

<211> 667

<212> DNA

<213> Homo sapiens

<400> 6

agcacaggac acagctgggt tctgaagctt ctgagttctg cagcctcacc tctgagaaaa 60

cctcttttcc accaatacca tgaagctctg cgtgactgtc ctgtctctcc tcatgctagt 120

agctgccttc tgctctccag cgctctcagc accaatgggc tcagaccctc ccaccgcctg 180

ctgcttttct tacaccgcga ggaagcttcc tcgcaacttt gtggtagatt actatgagac 240

cagcagcctc tgctcccagc cagctgtggt attccaaacc aaaagaagca agcaagtctg 300

tgctgatccc agtgaatcct gggtccagga gtacgtgtat gacctggaac tgaactgagc 360

tgctcagaga caggaagtct tcagggaagg tcacctgagc ccggatgctt ctccatgaga 420

cacatctcct ccatactcag gactcctctc cgcagttcct gtcccttctc ttaatttaat 480

cttttttatg tgccgtgtta ttgtattagg tgtcatttcc attatttata ttagtttagc 540

caaaggataa gtgtccccta tggggatggt ccactgtcac tgtttctctg ctgttgcaaa 600

tacatggata acacatttga ttctgtgtgt tttcataata aaactttaaa ataaaatgca 660

gacagtt 667

<210> 7

<211> 1237

<212> DNA

<213> Homo sapiens

<400> 7

gctgcagagg attcctgcag aggatcaaga cagcacgtgg acctcgcaca gcctctccca 60

caggtaccat gaaggtctcc gcggcagccc tcgctgtcat cctcattgct actgccctct 120

gcgctcctgc atctgcctcc ccatattcct cggacaccac accctgctgc tttgcctaca 180

ttgcccgccc actgccccgt gcccacatca aggagtattt ctacaccagt ggcaagtgct 240

ccaacccagc agtcgtcttt gtcacccgaa agaaccgcca agtgtgtgcc aacccagaga 300

agaaatgggt tcgggagtac atcaactctt tggagatgag ctaggatgga gagtccttga 360

acctgaactt acacaaattt gcctgtttct gcttgctctt gtcctagctt gggaggcttc 420

ccctcactat cctaccccac ccgctccttg aagggcccag attctaccac acagcagcag 480

ttacaaaaac cttccccagg ctggacgtgg tggctcacgc ctgtaatccc agcactttgg 540

gaggccaagg tgggtggatc acttgaggtc aggagttcga gaccagcctg gccaacatga 600

tgaaacccca tctctactaa aaatacaaaa aattagccgg gcgtggtagc gggcgcctgt 660

agtcccagct actcgggagg ctgaggcagg agaatggcgt gaacccggga ggcggagctt 720

gcagtgagcc gagatcgcgc cactgcactc cagcctgggc gacagagcga gactccgtct 780

caaaaaaaaa aaaaaaaaaa aaaatacaaa aattagccgg gcgtggtggc ccacgcctgt 840

aatcccagct actcgggagg ctaaggcagg aaaattgttt gaacccagga ggtggaggct 900

gcagtgagct gagattgtgc cacttcactc cagcctgggt gacaaagtga gactccgtca 960

caacaacaac aacaaaaagc ttccccaact aaagcctaga agagcttctg aggcgctgct 1020

ttgtcaaaag gaagtctcta ggttctgagc tctggctttg ccttggcttt gccagggctc 1080

tgtgaccagg aaggaagtca gcatgcctct agaggcaagg aggggaggaa cactgcactc 1140

ttaagcttcc gccgtctcaa cccctcacag gagcttactg gcaaacatga aaaatcggct 1200

taccattaaa gttctcaatg caaccataaa aaaaaaa 1237

<210> 8

<211> 851

<212> DNA

<213> Homo sapiens

<400> 8

agaatataac agcactccca aagaactggg tactcaacac tgagcagatc tgttctttga 60

gctaaaaacc atgtgctgta ccaagagttt gctcctggct gctttgatgt cagtgctgct 120

actccacctc tgcggcgaat cagaagcagc aagcaacttt gactgctgtc ttggatacac 180

agaccgtatt cttcatccta aatttattgt gggcttcaca cggcagctgg ccaatgaagg 240

ctgtgacatc aatgctatca tctttcacac aaagaaaaag ttgtctgtgt gcgcaaatcc 300

aaaacagact tgggtgaaat atattgtgcg tctcctcagt aaaaaagtca agaacatgta 360

aaaactgtgg cttttctgga atggaattgg acatagccca agaacagaaa gaaccttgct 420

ggggttggag gtttcacttg cacatcatgg agggtttagt gcttatctaa tttgtgcctc 480

actggacttg tccaattaat gaagttgatt catattgcat catagtttgc tttgtttaag 540

catcacatta aagttaaact gtattttatg ttatttatag ctgtaggttt tctgtgttta 600

gctatttaat actaattttc cataagctat tttggtttag tgcaaagtat aaaattatat 660

ttggggggga ataagattat atggactttc ttgcaagcaa caagctattt tttaaaaaaa 720

actatttaac attcttttgt ttatattgtt ttgtctccta aattgttgta attgcattat 780

aaaataagaa aaatattaat aagacaaata ttgaaaataa agaaacaaaa agttcttctg 840

ttaaaaaaaa a 851

<210> 9

<211> 2933

<212> DNA

<213> Homo sapiens

<400> 9

gcagacacct gggctgagac atacaggaca gagcatggat cgcctacaga ctgcactcct 60

ggttgtcctc gtcctccttg ctgtggcgct tcaagcaact gaggcaggcc cctacggcgc 120

caacatggaa gacagcgtct gctgccgtga ttacgtccgt taccgtctgc ccctgcgcgt 180

ggtgaaacac ttctactgga cctcagactc ctgcccgagg cctggcgtgg tgttgctaac 240

cttcagggat aaggagatct gtgccgatcc cagagtgccc tgggtgaaga tgattctcaa 300

taagctgagc caatgaagag cctactctga tgaccgtggc cttggctcct ccaggaaggc 360

tcaggagccc tacctccctg ccattatagc tgctccccgc cagaagcctg tgccaactct 420

ctgcattccc tgatctccat ccctgtggct gtcacccttg gtcacctccg tgctgtcact 480

gccatctccc ccctgacccc tctaacccat cctctgcctc cctccctgca gtcagagggt 540

cctgttccca tcagcgattc ccctgcttaa acccttccat gactccccac tgccctaagc 600

tgaggtcagt ctcccaagcc tggcatgtgg ccctctggat ctgggttcca tctctgtctc 660

cagcctgccc acttcccttc atgaatgttg ggttctagct ccctgttctc caaacccata 720

ctacacatcc cacttctggg tctttgcctg ggatgttgct gacacccaga aagtcccacc 780

acctgcacat gtgtagcccc accagccctc caaggcattg ctcgcccaag cagctggtaa 840

ttccatttca tgtattagat gtcccctggc cctctgtccc ctcttaataa ccctagtcac 900

agtctccgca gattcttggg atttgggggt tttctccccc acctctccac tagttggacc 960

aaggtttcta gctaagttac tctagtctcc aagcctctag catagagcac tgcagacagg 1020

ccctggctca gaatcagagc ccagaaagtg gctgcagaca aaatcaataa aactaatgtc 1080

cctcccctct ccctgccaaa aggcagttac atatcaatac agagactcaa ggtcactaga 1140

aatgggccag ctgggtcaat gtgaagcccc aaatttgccc agattcacct ttcttccccc 1200

actccctttt tttttttttt tttgagatgg agtttcgctc ttgtcaccca cgctggagtg 1260

caatggtgtg gtcttggctt attgaagcct ctgcctcctg ggttcaagtg attctcttgc 1320

ctcagcctcc tgagtagctg ggattacagg ttcctgctac cacgcccagc taatttttgt 1380

atttttagta gagacgaggc ttcaccatgt tggccaggct ggtctcgaac tcctgtcctc 1440

aggtaatccg cccacctcag cctcccaaag tgctgggatt acaggcgtga gccacagtgc 1500

ctggcctctt ccctctcccc accccccccc caactttttt ttttttttat ggcagggtct 1560

cactctgtcg cccaggctgg agtgcagtgg cgtgatctcg gctcactaca acctcgacct 1620

cctgggttca agcgattctc ccaccccagc ctcccaagta gctgggatta caggtgtgtg 1680

ccactacggc tggctaattt ttgtattttt agtagagaca ggtttcacca tattggccag 1740

gctggtcttg aactcctgac ctcaagtgat ccaccttcct tgtgctccca aagtgctgag 1800

attacaggcg tgagctatca cacccagcct cccccttttt ttcctaatag gagactcctg 1860

tacctttctt cgttttacct atgtgtcgtg tctgcttaca tttccttctc ccctcaggct 1920

ttttttgggt ggtcctccaa cctccaatac ccaggcctgg cctcttcaga gtacccccca 1980

ttccactttc cctgcctcct tccttaaata gctgacaatc aaattcatgc tatggtgtga 2040

aagactacct ttgacttggt attataagct ggagttatat atgtatttga aaacagagta 2100

aatacttaag aggccaaata gatgaatgga agaattttag gaactgtgag agggggacaa 2160

ggtggagctt tcctggccct gggaggaagc tggctgtggt agcgtagcgc tctctctctc 2220

tgtctgtggc aggaggcaaa gagtagggtg taattgagtg aaggaatcct gggtagagac 2280

cattctcagg tggttgggcc aggctaaaga ctgggatttg ggtctatcta tgcctttctg 2340

gctgattttt gtagagacgg ggttttgcca tgttacccag gctggtctca aactcctggg 2400

ctcaagcgat cctcctggct cagcctccca aagtgctggg attacaggcg tgagtcactg 2460

cgcctggctt cctcttcctc ttgagaaata ttcttttcat acagcaagta tgggacagca 2520

gtgtcccagg taaaggacat aaatgttaca agtgtctggt cctttctgag ggaggctggt 2580

gccgctctgc agggtatttg aacctgtgga attggaggag gccatttcac tccctgaacc 2640

cagcctgaca aatcacagtg agaatgttca ccttataggc ttgctgtggg gctcaggttg 2700

aaagtgtggg gagtgacact gcctaggcat ccagctcagt gtcatccagg gcctgtgtcc 2760

ctcccgaacc cagggtcaac ctgcctacca caggcactag aaggacgaat ctgcctactg 2820

cccatgaacg gggccctcaa gcgtcctggg atctccttct ccctcctgtc ctgtccttgc 2880

ccctcaggac tgctggaaaa taaatccttt aaaatagtaa aaaaaaaaaa aaa 2933

<210> 10

<211> 800

<212> DNA

<213> Homo sapiens

<400> 10

acacagagag aaaggctaaa gttctctgga ggatgtggct gcagagcctg ctgctcttgg 60

gcactgtggc ctgcagcatc tctgcacccg cccgctcgcc cagccccagc acgcagccct 120

gggagcatgt gaatgccatc caggaggccc ggcgtctcct gaacctgagt agagacactg 180

ctgctgagat gaatgaaaca gtagaagtca tctcagaaat gtttgacctc caggagccga 240

cctgcctaca gacccgcctg gagctgtaca agcagggcct gcggggcagc ctcaccaagc 300

tcaagggccc cttgaccatg atggccagcc actacaagca gcactgccct ccaaccccgg 360

aaacttcctg tgcaacccag attatcacct ttgaaagttt caaagagaac ctgaaggact 420

ttctgcttgt catccccttt gactgctggg agccagtcca ggagtgagac cggccagatg 480

aggctggcca agccggggag ctgctctctc atgaaacaag agctagaaac tcaggatggt 540

catcttggag ggaccaaggg gtgggccaca gccatggtgg gagtggcctg gacctgccct 600

gggccacact gaccctgata caggcatggc agaagaatgg gaatatttta tactgacaga 660

aatcagtaat atttatatat ttatattttt aaaatattta tttatttatt tatttaagtt 720

catattccat atttattcaa gatgttttac cgtaataatt attattaaaa atatgcttct 780

acttgaaaaa aaaaaaaaaa 800

<210> 11

<211> 3338

<212> DNA

<213> Homo sapiens

<400> 11

ataaaaagcc acagatctct ggcggcggca aggggacagc actgagctct gccgcctggc 60

tctagccgcc tgcctggccc ccgccgggac tcttgcccac cctcagccat ggctccgata 120

tctctgtcgt ggctgctccg cttggccacc ttctgccatc tgactgtcct gctggctgga 180

cagcaccacg gtgtgacgaa atgcaacatc acgtgcagca agatgacatc aaagatacct 240

gtagctttgc tcatccacta tcaacagaac caggcatcat gcggcaaacg cgcaatcatc 300

ttggagacga gacagcacag gctgttctgt gccgacccga aggagcaatg ggtcaaggac 360

gcgatgcagc atctggaccg ccaggctgct gccctaactc gaaatggcgg caccttcgag 420

aagcagatcg gcgaggtgaa gcccaggacc acccctgccg ccgggggaat ggacgagtct 480

gtggtcctgg agcccgaagc cacaggcgaa agcagtagcc tggagccgac tccttcttcc 540

caggaagcac agagggccct ggggacctcc ccagagctgc cgacgggcgt gactggttcc 600

tcagggacca ggctcccccc gacgccaaag gctcaggatg gagggcctgt gggcacggag 660

cttttccgag tgcctcccgt ctccactgcc gccacgtggc agagttctgc tccccaccaa 720

cctgggccca gcctctgggc tgaggcaaag acctctgagg ccccgtccac ccaggacccc 780

tccacccagg cctccactgc gtcctcccca gccccagagg agaatgctcc gtctgaaggc 840

cagcgtgtgt ggggtcaggg acagagcccc aggccagaga actctctgga gcgggaggag 900

atgggtcccg tgccagcgca cacggatgcc ttccaggact gggggcctgg cagcatggcc 960

cacgtctctg tggtccctgt ctcctcagaa gggaccccca gcagggagcc agtggcttca 1020

ggcagctgga cccctaaggc tgaggaaccc atccatgcca ccatggaccc ccagaggctg 1080

ggcgtcctta tcactcctgt ccctgacgcc caggctgcca cccggaggca ggcggtgggg 1140

ctgctggcct tccttggcct cctcttctgc ctgggggtgg ccatgttcac ctaccagagc 1200

ctccagggct gccctcgaaa gatggcagga gagatggcgg agggccttcg ctacatcccc 1260

cggagctgtg gtagtaattc atatgtcctg gtgcccgtgt gaactcctct ggcctgtgtc 1320

tagttgtttg attcagacag ctgcctggga tccctcatcc tcatacccac ccccacccaa 1380

gggcctggcc tgagctggga tgattggagg ggggaggtgg gatcctccag gtgcacaagc 1440

tccaagctcc caggcattcc ccaggaggcc agccttgacc attctccacc tgccagggac 1500

agagggggtg gcctcccaac tcaccccagc cccaaaactc tcctctgctg ctggctggtt 1560

agaggttccc tttgacgcca tcccagcccc aatgaacaat tatttattaa atgcccagcc 1620

ccttctgacc catgctgccc tgtgagtact acagtcctcc catctcacac atgagcatca 1680

ggccaggccc tctgcccact ccctgcaacc tgattgtgtc tcttggtcct gctgcagttg 1740

ccagtcaccc cggccacctg cggtgctatc tcccccagcc ccatcctctg tacagagccc 1800

acgcccccac tggtgacatg tcttttcttg catgaggcta gtgtggtgtt tcctggcact 1860

gcttccagtg aggctctgcc cttggttagg cattgtggga aggggagata agggtatctg 1920

gtgactttcc tctttggtct acactgtgct gagtctgaag gctgggttct gatcctagtt 1980

ccaccatcaa gccaccaaca tactcccatc tgtgaaagga aagagggagg taaggaatac 2040

ctgtccccct gacaacactc attgacctga ggcccttctc tccagcccct ggatgcagcc 2100

tcacagtcct taccagcaga gcaccttaga cagtccctgc caatggacta acttgtcttt 2160

ggaccctgag gcccagaggg cctgcaaggg agtgagttga tagcacagac cctgccctgt 2220

gggcccccaa atggaaatgg gcagagcaga gaccatccct gaaggccccg cccaggctta 2280

gtcactgaga cagcccgggc tctgcctccc atcacccgct aagagggagg gagggctcca 2340

gacacatgtc caagaagccc aggaaaggct ccaggagcag ccacattcct gatgcttctt 2400

cagagactcc tgcaggcagc caggccacaa gacccttgtg gtcccacccc acacacgcca 2460

gattctttcc tgaggctggg ctcccttccc acctctctca ctccttgaaa acactgttct 2520

ctgccctcca agaccttctc cttcaccttt gtccccaccg cagacaggac cagggatttc 2580

catgatgttt tccatgagtc ccctgtttgt ttctgaaagg gacgctaccc gggaaggggg 2640

ctgggacatg ggaaagggga agttgtaggc ataaagtcag gggttccctt ttttggctgc 2700

tgaaggctcg agcatgcctg gatggggctg caccggctgg cctggcccct cagggtccct 2760

ggtggcagct cacctctccc ttggattgtc cccgaccctt gccgtctacc tgaggggcct 2820

cttatgggct gggttctacc caggtgctag gaacactcct tcacagatgg gtgcttggag 2880

gaaggaaacc cagctctggt ccatagagag caagacgctg tgctgccctg cccacctggc 2940

ctctgcactc ccctgctggg tgtggcgcag catattcagg aagctcaggg cctggctcag 3000

gtggggtcac tctggcagct cagagagggt gggagtgggc ccaatgcact ttgttctggc 3060

tcttccaggc tgggagagcc ttccaggggt gggacaccct gtgatggggc cctgcctcct 3120

ttgtgaggaa gccgctgggg ccagttggtc ccccttccat ggactttgtt agtttctcca 3180

agcaggacat ggacaaggat gatctaggaa gactttggaa agagtaggaa gactttggaa 3240

agacttttcc aaccctcatc accaacgtct gtgccatttt gtattttact aataaaattt 3300

aaaagtcttg tgaatcaaaa aaaaaaaaaa aaaaaaaa 3338

<210> 12

<211> 1184

<212> DNA

<213> Homo sapiens

<400> 12

cacagagccc gggccgcagg cacctcctcg ccagctcttc cgctcctctc acagccgcca 60

gacccgcctg ctgagcccca tggcccgcgc tgctctctcc gccgccccca gcaatccccg 120

gctcctgcga gtggcactgc tgctcctgct cctggtagcc gctggccggc gcgcagcagg 180

agcgtccgtg gccactgaac tgcgctgcca gtgcttgcag accctgcagg gaattcaccc 240

caagaacatc caaagtgtga acgtgaagtc ccccggaccc cactgcgccc aaaccgaagt 300

catagccaca ctcaagaatg ggcggaaagc ttgcctcaat cctgcatccc ccatagttaa 360

gaaaatcatc gaaaagatgc tgaacagtga caaatccaac tgaccagaag ggaggaggaa 420

gctcactggt ggctgttcct gaaggaggcc ctgcccttat aggaacagaa gaggaaagag 480

agacacagct gcagaggcca cctggattgt gcctaatgtg tttgagcatc gcttaggaga 540

agtcttctat ttatttattt attcattagt tttgaagatt ctatgttaat attttaggtg 600

taaaataatt aagggtatga ttaactctac ctgcacactg tcctattata ttcattcttt 660

ttgaaatgtc aaccccaagt tagttcaatc tggattcata tttaatttga aggtagaatg 720

ttttcaaatg ttctccagtc attatgttaa tatttctgag gagcctgcaa catgccagcc 780

actgtgatag aggctggcgg atccaagcaa atggccaatg agatcattgt gaaggcaggg 840

gaatgtatgt gcacatctgt tttgtaactg tttagatgaa tgtcagttgt tatttattga 900

aatgatttca cagtgtgtgg tcaacatttc tcatgttgaa actttaagaa ctaaaatgtt 960

ctaaatatcc cttggacatt ttatgtcttt cttgtaaggc atactgcctt gtttaatggt 1020

agttttacag tgtttctggc ttagaacaaa ggggcttaat tattgatgtt ttcatagaga 1080

atataaaaat aaagcactta tagaaaaaac tcgtttgatt tttgggggga aacaagggct 1140

acctttactg gaaaatctgg tgatttataa aaaaaaaaaa aaaa 1184

<210> 13

<211> 1234

<212> DNA

<213> Homo sapiens

<400> 13

gagctccggg aatttccctg gcccgggact ccgggctttc cagccccaac catgcataaa 60

aggggttcgc cgttctcgga gagccacaga gcccgggcca caggcagctc cttgccagct 120

ctcctcctcg cacagccgct cgaaccgcct gctgagcccc atggcccgcg ccacgctctc 180

cgccgccccc agcaatcccc ggctcctgcg ggtggcgctg ctgctcctgc tcctggtggc 240

cgccagccgg cgcgcagcag gagcgcccct ggccactgaa ctgcgctgcc agtgcttgca 300

gaccctgcag ggaattcacc tcaagaacat ccaaagtgtg aaggtgaagt cccccggacc 360

ccactgcgcc caaaccgaag tcatagccac actcaagaat gggcagaaag cttgtctcaa 420

ccccgcatcg cccatggtta agaaaatcat cgaaaagatg ctgaaaaatg gcaaatccaa 480

ctgaccagaa ggaaggagga agcttattgg tggctgttcc tgaaggaggc cctgccctta 540

caggaacaga agaggaaaga gagacacagc tgcagaggcc acctggattg cgcctaatgt 600

gtttgagcat cacttaggag aagtcttcta tttatttatt tatttattta tttgtttgtt 660

ttagaagatt ctatgttaat attttatgtg taaaataagg ttatgattga atctacttgc 720

acactctccc attatattta ttgtttattt taggtcaaac ccaagttagt tcaatcctga 780

ttcatattta atttgaagat agaaggtttg cagatattct ctagtcattt gttaatattt 840

cttcgtgatg acatatcaca tgtcagccac tgtgatagag gctgaggaat ccaagaaaat 900

ggccagtgag atcaatgtga cggcagggaa atgtatgtgt gtctattttg taactgtaaa 960

gatgaatgtc agttgttatt tattgaaatg atttcacagt gtgtggtcaa catttctcat 1020

gttgaagctt taagaactaa aatgttctaa atatcccttg gacattttat gtctttcttg 1080

taaggcatac tgccttgttt aatgttaatt atgcagtgtt tccctctgtg ttagagcaga 1140

gaggtttcga tatttattga tgttttcaca aagaacagga aaataaaata tttaaaaata 1200

taaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaa 1234

<210> 14

<211> 1166

<212> DNA

<213> Homo sapiens

<400> 14

gctccgggaa tttccctggc ccggccgctc cgggctttcc agtctcaacc atgcataaaa 60

agggttcgcc gatcttgggg agccacacag cccgggtcgc aggcacctcc ccgccagctc 120

tcccgcttct cgcacagctt cccgacgcgt ctgctgagcc ccatggccca cgccacgctc 180

tccgccgccc ccagcaatcc ccggctcctg cgggtggcgc tgctgctcct gctcctggtg 240

gccgccagcc ggcgcgcagc aggagcgtcc gtggtcactg aactgcgctg ccagtgcttg 300

cagacactgc agggaattca cctcaagaac atccaaagtg tgaatgtaag gtcccccgga 360

ccccactgcg cccaaaccga agtcatagcc acactcaaga atgggaagaa agcttgtctc 420

aaccccgcat cccccatggt tcagaaaatc atcgaaaaga tactgaacaa ggggagcacc 480

aactgacagg agagaagtaa gaagcttatc agcgtatcat tgacacttcc tgcagggtgg 540

tccctgccct taccagagct gaaaatgaaa aagagaacag cagctttcta gggacagctg 600

gaaaggactt aatgtgtttg actatttctt acgagggttc tacttattta tgtatttatt 660

tttgaaagct tgtattttaa tattttacat gctgttattt aaagatgtga gtgtgtttca 720

tcaaacatag ctcagtcctg attatttaat tggaatatga tgggttttaa atgtgtcatt 780

aaactaatat ttagtgggag accataatgt gtcagccacc ttgataaatg acagggtggg 840

gaactggagg gtggggggat tgaaatgcaa gcaattagtg gatcactgtt agggtaaggg 900

aatgtatgta cacatctatt ttttatactt tttttttaaa aaaagaatgt cagttgttat 960

ttattcaaat tatctcacat tatgtgttca acatttttat gctgaagttt cccttagaca 1020

ttttatgtct tgcttgtagg gcataatgcc ttgtttaatg tccattctgc agcgtttctc 1080

tttcccttgg aaaagagaat ttatcattac tgttacattt gtacaaatga catgataata 1140

aaagttttat gaaaaaaaaa aaaaaa 1166

<210> 15

<211> 1227

<212> DNA

<213> Homo sapiens

<400> 15

ctttgcagat aaatatggca cactagcccc acgttttctg agacattcct caattgctta 60

gacatattct gagcctacag cagaggaacc tccagtctca gcaccatgaa tcaaactgcc 120

attctgattt gctgccttat ctttctgact ctaagtggca ttcaaggagt acctctctct 180

agaactgtac gctgtacctg catcagcatt agtaatcaac ctgttaatcc aaggtcttta 240

gaaaaacttg aaattattcc tgcaagccaa ttttgtccac gtgttgagat cattgctaca 300

atgaaaaaga agggtgagaa gagatgtctg aatccagaat cgaaggccat caagaattta 360

ctgaaagcag ttagcaagga aaggtctaaa agatctcctt aaaaccagag gggagcaaaa 420

tcgatgcagt gcttccaagg atggaccaca cagaggctgc ctctcccatc acttccctac 480

atggagtata tgtcaagcca taattgttct tagtttgcag ttacactaaa aggtgaccaa 540

tgatggtcac caaatcagct gctactactc ctgtaggaag gttaatgttc atcatcctaa 600

gctattcagt aataactcta ccctggcact ataatgtaag ctctactgag gtgctatgtt 660

cttagtggat gttctgaccc tgcttcaaat atttccctca cctttcccat cttccaaggg 720

tactaaggaa tctttctgct ttggggttta tcagaattct cagaatctca aataactaaa 780

aggtatgcaa tcaaatctgc tttttaaaga atgctcttta cttcatggac ttccactgcc 840

atcctcccaa ggggcccaaa ttctttcagt ggctacctac atacaattcc aaacacatac 900

aggaaggtag aaatatctga aaatgtatgt gtaagtattc ttatttaatg aaagactgta 960

caaagtagaa gtcttagatg tatatatttc ctatattgtt ttcagtgtac atggaataac 1020

atgtaattaa gtactatgta tcaatgagta acaggaaaat tttaaaaata cagatagata 1080

tatgctctgc atgttacata agataaatgt gctgaatggt tttcaaaata aaaatgaggt 1140

actctcctgg aaatattaag aaagactatc taaatgttga aagatcaaaa ggttaataaa 1200

gtaattataa ctaagaaaaa aaaaaaa 1227

<210> 16

<211> 460

<212> DNA

<213> Homo sapiens

<400> 16

gtggctgaat tctaacctct gtaatgagca ttgcacccaa taccagttct gaactctacc 60

tggtgaccag ggaccaggac ctttataagg tggaaggctt gatgtcctcc ccagactcag 120

ctcctggtga agctcccagc catcagccat gagggtcttg tatctcctct tctcgttcct 180

cttcatattc ctgatgcctc ttccaggtgt ttttggtggt ataggcgatc ctgttacctg 240

ccttaagagt ggagccatat gtcatccagt cttttgccct agaaggtata aacaaattgg 300

cacctgtggt ctccctggaa caaaatgctg caaaaagcca tgaggaggcc aagaagctgc 360

tgtggctgat gcggattcag aaagggctcc ctcatcagag acgtgcgaca tgtaaaccaa 420

attaaactat ggtgtccaaa gatacgcaaa aaaaaaaaaa 460

<210> 17

<211> 1907

<212> DNA

<213> Homo sapiens

<400> 17

agaatcagag agagagagat agagaaagag aaagacagag gtgtttccct tagctatgga 60

aactctataa gagagatcca gcttgcctcc tcttgagcag tcagcaacag ggtcccgtcc 120

ttgacacctc agcctctaca ggactgagaa gaagtaaaac cgtttgctgg ggctggcctg 180

actcaccagc tgccatgcag cagcccttca attacccata tccccagatc tactgggtgg 240

acagcagtgc cagctctccc tgggcccctc caggcacagt tcttccctgt ccaacctctg 300

tgcccagaag gcctggtcaa aggaggccac caccaccacc gccaccgcca ccactaccac 360

ctccgccgcc gccgccacca ctgcctccac taccgctgcc acccctgaag aagagaggga 420

accacagcac aggcctgtgt ctccttgtga tgtttttcat ggttctggtt gccttggtag 480

gattgggcct ggggatgttt cagctcttcc acctacagaa ggagctggca gaactccgag 540

agtctaccag ccagatgcac acagcatcat ctttggagaa gcaaataggc caccccagtc 600

caccccctga aaaaaaggag ctgaggaaag tggcccattt aacaggcaag tccaactcaa 660

ggtccatgcc tctggaatgg gaagacacct atggaattgt cctgctttct ggagtgaagt 720

ataagaaggg tggccttgtg atcaatgaaa ctgggctgta ctttgtatat tccaaagtat 780

acttccgggg tcaatcttgc aacaacctgc ccctgagcca caaggtctac atgaggaact 840

ctaagtatcc ccaggatctg gtgatgatgg aggggaagat gatgagctac tgcactactg 900

ggcagatgtg ggcccgcagc agctacctgg gggcagtgtt caatcttacc agtgctgatc 960

atttatatgt caacgtatct gagctctctc tggtcaattt tgaggaatct cagacgtttt 1020

tcggcttata taagctctaa gagaagcact ttgggattct ttccattatg attctttgtt 1080

acaggcaccg agaatgttgt attcagtgag ggtcttctta catgcatttg aggtcaagta 1140

agaagacatg aaccaagtgg accttgagac cacagggttc aaaatgtctg tagctcctca 1200

actcacctaa tgtttatgag ccagacaaat ggaggaatat gacggaagaa catagaactc 1260

tgggctgcca tgtgaagagg gagaagcatg aaaaagcagc taccaggtgt tctacactca 1320

tcttagtgcc tgagagtatt taggcagatt gaaaaggaca ccttttaact cacctctcaa 1380

ggtgggcctt gctacctcaa gggggactgt ctttcagata catggttgtg acctgaggat 1440

ttaagggatg gaaaaggaag actagaggct tgcataataa gctaaagagg ctgaaagagg 1500

ccaatgcccc actggcagca tcttcacttc taaatgcata tcctgagcca tcggtgaaac 1560

taacagataa gcaagagaga tgttttgggg actcatttca ttcctaacac agcatgtgta 1620

tttccagtgc aattgtaggg gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt gtatgactaa 1680

agagagaatg tagatattgt gaagtacata ttaggaaaat atgggttgca tttggtcaag 1740

attttgaatg cttcctgaca atcaactcta atagtgctta aaaatcattg attgtcagct 1800

actaatgatg ttttcctata atataataaa tatttatgta gatgtgcatt tttgtgaaat 1860

gaaaacatgt aataaaaagt atatgttagg atacaaaaaa aaaaaaa 1907

<210> 18

<211> 3823

<212> DNA

<213> Homo sapiens

<400> 18

ataaaacctg gagcgcagga tcgcgcccag gagcggcgag ctagcggacg caaagactgg 60

gcatgctccg cggcggcgca ggttttggtc acaagtagga agaagccagt gcaccagacc 120

ggcaaagaga agcgggagcc gccgcggcag cgcggccgtg gggtccgccg ccgccgcatc 180

ggagcgggag gaggagcagc ggggagggcg aggccgccgg gccgagagcc gtcccgcctg 240

ctctcggtct tctgccttcg cctccgcgcg gtgcgtcgga cccagggtct gtcacctggg 300

cgccaggggc cgccgccggg gagccggagc gggcaggacc ctccctccgc cgactgcggc 360

ccgagagcgc ccccgcgggg tggagcggca gccgccttct gcgggcggct gagtgtccgt 420

ctcgcgcccg gagcgggcga ccgccgtcag cccggaggag gaggaggagg aggagggggc 480

ggccatgggg ctgctgtccc agggctcgcc gctgagctgg gaggaaacca agcgccatgc 540

cgaccacgtg cggcggcacg ggatcctcca gttcctgcac atctaccacg ccgtcaagga 600

ccggcacaag gacgttctca agtggggcga tgaggtggaa tacatgttgg tatcttttga 660

tcatgaaaat aaaaaagtcc ggttggtcct gtctggggag aaagttcttg aaactctgca 720

agagaagggg gaaaggacaa acccaaacca tcctaccctt tggagaccag agtatgggag 780

ttacatgatt gaagggacac caggacagcc ctacggagga acaatgtccg agttcaatac 840

agttgaggcc aacatgcgaa aacgccggaa ggaggctact tctatattag aagaaaatca 900

ggctctttgc acaataactt catttcccag attaggctgt cctgggttca cactgcccga 960

ggtcaaaccc aacccagtgg aaggaggagc ttccaagtcc ctcttctttc cagatgaagc 1020

aataaacaag caccctcgct tcagtacctt aacaagaaat atccgacata ggagaggaga 1080

aaaggttgtc atcaatgtac caatatttaa ggacaagaat acaccatctc catttataga 1140

aacatttact gaggatgatg aagcttcaag ggcttctaag ccggatcata tttacatgga 1200

tgccatggga tttggaatgg gcaattgctg tctccaggtg acattccaag cctgcagtat 1260

atctgaggcc agataccttt atgatcagtt ggctactatc tgtccaattg ttatggcttt 1320

gagtgctgca tctccctttt accgaggcta tgtgtcagac attgattgtc gctggggagt 1380

gatttctgca tctgtagatg atagaactcg ggaggagcga ggactggagc cattgaagaa 1440

caataactat aggatcagta aatcccgata tgactcaata gacagctatt tatctaagtg 1500

tggtgagaaa tataatgaca tcgacttgac gatagataaa gagatctacg aacagctgtt 1560

gcaggaaggc attgatcatc tcctggccca gcatgttgct catctcttta ttagagaccc 1620

actgacactg tttgaagaga aaatacacct ggatgatgct aatgagtctg accattttga 1680

gaatattcag tccacaaatt ggcagacaat gagatttaag ccccctcctc caaactcaga 1740

cattggatgg agagtagaat ttcgacccat ggaggtgcaa ttaacagact ttgagaactc 1800

tgcctatgtg gtgtttgtgg tactgctcac cagagtgatc ctttcctaca aattggattt 1860

tctcattcca ctgtcaaagg ttgatgagaa catgaaggta gcacagaaaa gagatgctgt 1920

cttgcaggga atgttttatt tcaggaaaga tatttgcaaa ggtggcaatg cagtggtgga 1980

tggttgtggc aaggcccaga acagcacgga gctcgctgca gaggagtaca ccctcatgag 2040

catagacacc atcatcaatg ggaaggaagg tgtgtttcct ggactgatcc caattctgaa 2100

ctcttacctt gaaaacatgg aagtggatgt ggacaccaga tgtagtattc tgaactacct 2160

aaagctaatt aagaagagag catctggaga actaatgaca gttgccagat ggatgaggga 2220

gtttatcgca aaccatcctg actacaagca agacagtgtc ataactgatg aaatgaatta 2280

tagccttatt ttgaagtgta accaaattgc aaatgaatta tgtgaatgcc cagagttact 2340

tggatcagca tttaggaaag taaaatatag tggaagtaaa actgactcat ccaactagac 2400

attctacaga aagaaaaatg cattattgac gaactggcta cagtaccatg cctctcagcc 2460

agcccgtgtg tataatatga agaccaaatg atagaactgt actgttttct gggccagtga 2520

gccagaaatt gattaaggct ttctttggta ggtaaatcta gagtttatac agtgtacatg 2580

tacatagtaa agtatttttg attaacaatg tattttaata acatatctaa agtcatcatg 2640

aactggcttg tacattttta aattcttact ctggagcaac ctactgtcta agcagttttg 2700

taaatgtact ggtaattgta caatacttgc attccagagt taaaatgttt actgtaaatt 2760

tttgttcttt taaagactac ctgggacctg atttattgaa atttttctct ttaaaaacat 2820

tttctctcgt taattttcct ttgtcatttc ctttgttgtc tacattaaat cacttgaatc 2880

cattgaaagt gcttcaaggg taatcttggg tttctagcac cttatctatg atgtttcttt 2940

tgcaattgga ataatcactt ggtcaccttg ccccaagctt tcccctctga ataaataccc 3000

attgaactct gatggctgtt atcaaaggaa cttttctttg tttaaatttg ctgatgcagg 3060

aattaagttt aaacacaact ctatagaaag aaaggagatt attacccaga attcacatgt 3120

agtgattatt aaggacaatt ttttttttta actaaaaaag ttggcggcag gggtgggggg 3180

tggcaatcat ttttcttcct atacatacaa aggatattgt caaaaatggc gttcttctct 3240

tgtggcctgt tattctgatt gctgctgtat acagttttgt cactctttag tttttagtta 3300

agcatactga tagactttcc tctaaaagcc attcactcca gattttacct ggggaatatt 3360

ctacatactg cttactttct ctataaaact catcaataaa tcatgaaagg cactgagttt 3420

tgtaaatcag gaccctaaat gtttaattgt aaataagttt cagataatta ttatagcttt 3480

gcgttgaagt ttgttgtttt ttttctcaac tagttaagtc aactgcttct gaaataactc 3540

tgtattgtag attatgcaga tctttacagg cataaatatt taaactgtaa tatgctaact 3600

tgaagagatt gcaataaagc tgcttcagct aaccctgttt atgtttaaat actagggttt 3660

gttctatatt ttatacatgc attttggatg attaaagaat gcctggtttt cgtttgcaat 3720

ttgcttgtgt aaatcaggtt gtaaaaaggc agataaattg aaatgtttgt ggtatgagga 3780

aataaaagaa tggaattagc tttcattcag aaaaaaaaaa aaa 3823

<210> 19

<211> 3249

<212> DNA

<213> Homo sapiens

<400> 19

caagcttagc ctggccggga aacgggaggc gtggaggccg ggagcagccc ccggggtcat 60

cgccctgcca ccgccgcccg attgctttag cttggaaatt ccggagctga agcggccagc 120

gagggaggat gaccctctcg gcccgggcac cctgtcagtc cggaaataac tgcagcattt 180

gttccggagg ggaaggcgcg aggtttccgg gaaagcagca ccgccccttg gcccccaggt 240

ggctagcgct ataaaggatc acgcgcccca gtcgacgctg agctcctctg ctactcagag 300

ttgcaacctc agcctcgcta tggctcccag cagcccccgg cccgcgctgc ccgcactcct 360

ggtcctgctc ggggctctgt tcccaggacc tggcaatgcc cagacatctg tgtccccctc 420

aaaagtcatc ctgccccggg gaggctccgt gctggtgaca tgcagcacct cctgtgacca 480

gcccaagttg ttgggcatag agaccccgtt gcctaaaaag gagttgctcc tgcctgggaa 540

caaccggaag gtgtatgaac tgagcaatgt gcaagaagat agccaaccaa tgtgctattc 600

aaactgccct gatgggcagt caacagctaa aaccttcctc accgtgtact ggactccaga 660

acgggtggaa ctggcacccc tcccctcttg gcagccagtg ggcaagaacc ttaccctacg 720

ctgccaggtg gagggtgggg caccccgggc caacctcacc gtggtgctgc tccgtgggga 780

gaaggagctg aaacgggagc cagctgtggg ggagcccgct gaggtcacga ccacggtgct 840

ggtgaggaga gatcaccatg gagccaattt ctcgtgccgc actgaactgg acctgcggcc 900

ccaagggctg gagctgtttg agaacacctc ggccccctac cagctccaga cctttgtcct 960

gccagcgact cccccacaac ttgtcagccc ccgggtccta gaggtggaca cgcaggggac 1020

cgtggtctgt tccctggacg ggctgttccc agtctcggag gcccaggtcc acctggcact 1080

gggggaccag aggttgaacc ccacagtcac ctatggcaac gactccttct cggccaaggc 1140

ctcagtcagt gtgaccgcag aggacgaggg cacccagcgg ctgacgtgtg cagtaatact 1200

ggggaaccag agccaggaga cactgcagac agtgaccatc tacagctttc cggcgcccaa 1260

cgtgattctg acgaagccag aggtctcaga agggaccgag gtgacagtga agtgtgaggc 1320

ccaccctaga gccaaggtga cgctgaatgg ggttccagcc cagccactgg gcccgagggc 1380

ccagctcctg ctgaaggcca ccccagagga caacgggcgc agcttctcct gctctgcaac 1440

cctggaggtg gccggccagc ttatacacaa gaaccagacc cgggagcttc gtgtcctgta 1500

tggcccccga ctggacgaga gggattgtcc gggaaactgg acgtggccag aaaattccca 1560

gcagactcca atgtgccagg cttgggggaa cccattgccc gagctcaagt gtctaaagga 1620

tggcactttc ccactgccca tcggggaatc agtgactgtc actcgagatc ttgagggcac 1680

ctacctctgt cgggccagga gcactcaagg ggaggtcacc cgcaaggtga ccgtgaatgt 1740

gctctccccc cggtatgaga ttgtcatcat cactgtggta gcagccgcag tcataatggg 1800

cactgcaggc ctcagcacgt acctctataa ccgccagcgg aagatcaaga aatacagact 1860

acaacaggcc caaaaaggga cccccatgaa accgaacaca caagccacgc ctccctgaac 1920

ctatcccggg acagggcctc ttcctcggcc ttcccatatt ggtggcagtg gtgccacact 1980

gaacagagtg gaagacatat gccatgcagc tacacctacc ggccctggga cgccggagga 2040

cagggcattg tcctcagtca gatacaacag catttggggc catggtacct gcacacctaa 2100

aacactaggc cacgcatctg atctgtagtc acatgactaa gccaagagga aggagcaaga 2160

ctcaagacat gattgatgga tgttaaagtc tagcctgatg agaggggaag tggtggggga 2220

gacatagccc caccatgagg acatacaact gggaaatact gaaacttgct gcctattggg 2280

tatgctgagg ccccacagac ttacagaaga agtggccctc catagacatg tgtagcatca 2340

aaacacaaag gcccacactt cctgacggat gccagcttgg gcactgctgt ctactgaccc 2400

caacccttga tgatatgtat ttattcattt gttattttac cagctattta ttgagtgtct 2460

tttatgtagg ctaaatgaac ataggtctct ggcctcacgg agctcccagt cctaatcaca 2520

ttcaaggtca ccaggtacag ttgtacaggt tgtacactgc aggagagtgc ctggcaaaaa 2580

gatcaaatgg ggctgggact tctcattggc caacctgcct ttccccagaa ggagtgattt 2640

ttctatcggc acaaaagcac tatatggact ggtaatggtt acaggttcag agattaccca 2700

gtgaggcctt attcctccct tccccccaaa actgacacct ttgttagcca cctccccacc 2760

cacatacatt tctgccagtg ttcacaatga cactcagcgg tcatgtctgg acatgagtgc 2820

ccagggaata tgcccaagct atgccttgtc ctcttgtcct gtttgcattt cactgggagc 2880

ttgcactatg cagctccagt ttcctgcagt gatcagggtc ctgcaagcag tggggaaggg 2940

ggccaaggta ttggaggact ccctcccagc tttggaagcc tcatccgcgt gtgtgtgtgt 3000

gtgtatgtgt agacaagctc tcgctctgtc acccaggctg gagtgcagtg gtgcaatcat 3060

ggttcactgc agtcttgacc ttttgggctc aagtgatcct cccacctcag cctcctgagt 3120

agctgggacc ataggctcac aacaccacac ctggcaaatt tgattttttt tttttttcca 3180

gagacggggt ctcgcaacat tgcccagact tcctttgtgt tagttaataa agctttctca 3240

actgccaaa 3249

<210> 20

<211> 1254

<212> DNA

<213> Homo sapiens

<400> 20

ctcacttggc cttacactcc gctcggctca ccatgtgtca ctctcgcagc tgccacccga 60

ccatgaccat cctgcaggcc ccgaccccgg ccccctccac catcccggga ccccggcggg 120

gctccggtcc tgagatcttc accttcgacc ctctcccgga gcccgcagcg gcccctgccg 180

ggcgccccag cgcctctcgc gggcaccgaa agcgcagccg cagggttctc taccctcgag 240

tggtccggcg ccagctgcca gtcgaggaac cgaacccagc caaaaggctt ctctttctgc 300

tgctcaccat cgtcttctgc cagatcctga tggctgaaga gggtgtgccg gcgcccctgc 360

ctccagagga cgcccctaac gccgcatccc tggcgcccac ccctgtgtcc gccgtcctcg 420

agccctttaa tctgacttcg gagccctcgg actacgctct ggacctcagc actttcctcc 480

agcaacaccc ggccgccttc taactgtgac tccccgcact ccccaaaaag aatccgaaaa 540

accacaaaga aacaccaggc gtacctggtg cgcgagagcg tatccccaac tgggacttcc 600

gaggcaactt gaactcagaa cactacagcg gagacgccac ccggtgcttg aggcgggacc 660

gaggcgcaca gagaccgagg cgcatagaga ccgaggcaca gcccagctgg ggctaggccc 720

ggtgggaagg agagcgtcgt taatttattt cttattgctc ctaattaata tttatatgta 780

tttatgtacg tcctcctagg tgatggagat gtgtacgtaa tatttatttt aacttatgca 840

agggtgtgag atgttccccc tgctgtaaat gcaggtctct tggtatttat tgagctttgt 900

gggactggtg gaagcaggac acctggaact gcggcaaagt aggagaagaa atggggagga 960

ctcgggtggg ggaggacgtc ccggctggga tgaagtctgg tggtgggtcg taagtttagg 1020

aggtgactgc atcctccagc atctcaactc cgtctgtcta ctgtgtgaga cttcggcgga 1080

ccattaggaa tgagatccgt gagatccttc catcttcttg aagtcgcctt tagggtggct 1140

gcgaggtaga gggttggggg ttggtgggct gtcacggagc gactgtcgag atcgcctagt 1200

atgttctgtg aacacaaata aaattgattt actgtctgca aaaaaaaaaa aaaa 1254

<210> 21

<211> 840

<212> DNA

<213> Homo sapiens

<400> 21

acattctaac tgcaaccttt cgaagccttt gctctggcac aacaggtagt aggcgacact 60

gttcgtgttg tcaacatgac caacaagtgt ctcctccaaa ttgctctcct gttgtgcttc 120

tccactacag ctctttccat gagctacaac ttgcttggat tcctacaaag aagcagcaat 180

tttcagtgtc agaagctcct gtggcaattg aatgggaggc ttgaatactg cctcaaggac 240

aggatgaact ttgacatccc tgaggagatt aagcagctgc agcagttcca gaaggaggac 300

gccgcattga ccatctatga gatgctccag aacatctttg ctattttcag acaagattca 360

tctagcactg gctggaatga gactattgtt gagaacctcc tggctaatgt ctatcatcag 420

ataaaccatc tgaagacagt cctggaagaa aaactggaga aagaagattt caccagggga 480

aaactcatga gcagtctgca cctgaaaaga tattatggga ggattctgca ttacctgaag 540

gccaaggagt acagtcactg tgcctggacc atagtcagag tggaaatcct aaggaacttt 600

tacttcatta acagacttac aggttacctc cgaaactgaa gatctcctag cctgtgcctc 660

tgggactgga caattgcttc aagcattctt caaccagcag atgctgttta agtgactgat 720

ggctaatgta ctgcatatga aaggacacta gaagattttg aaatttttat taaattatga 780

gttattttta tttatttaaa ttttattttg gaaaataaat tatttttggt gcaaaagtca 840

<210> 22

<211> 2347

<212> DNA

<213> Homo sapiens

<400> 22

ctgtttcagg gccattggac tctccgtcct gcccagagca agatgtgtca ccagcagttg 60

gtcatctctt ggttttccct ggtttttctg gcatctcccc tcgtggccat atgggaactg 120

aagaaagatg tttatgtcgt agaattggat tggtatccgg atgcccctgg agaaatggtg 180

gtcctcacct gtgacacccc tgaagaagat ggtatcacct ggaccttgga ccagagcagt 240

gaggtcttag gctctggcaa aaccctgacc atccaagtca aagagtttgg agatgctggc 300

cagtacacct gtcacaaagg aggcgaggtt ctaagccatt cgctcctgct gcttcacaaa 360

aaggaagatg gaatttggtc cactgatatt ttaaaggacc agaaagaacc caaaaataag 420

acctttctaa gatgcgaggc caagaattat tctggacgtt tcacctgctg gtggctgacg 480

acaatcagta ctgatttgac attcagtgtc aaaagcagca gaggctcttc tgacccccaa 540

ggggtgacgt gcggagctgc tacactctct gcagagagag tcagagggga caacaaggag 600

tatgagtact cagtggagtg ccaggaggac agtgcctgcc cagctgctga ggagagtctg 660

cccattgagg tcatggtgga tgccgttcac aagctcaagt atgaaaacta caccagcagc 720

ttcttcatca gggacatcat caaacctgac ccacccaaga acttgcagct gaagccatta 780

aagaattctc ggcaggtgga ggtcagctgg gagtaccctg acacctggag tactccacat 840

tcctacttct ccctgacatt ctgcgttcag gtccagggca agagcaagag agaaaagaaa 900

gatagagtct tcacggacaa gacctcagcc acggtcatct gccgcaaaaa tgccagcatt 960

agcgtgcggg cccaggaccg ctactatagc tcatcttgga gcgaatgggc atctgtgccc 1020

tgcagttagg ttctgatcca ggatgaaaat ttggaggaaa agtggaagat attaagcaaa 1080

atgtttaaag acacaacgga atagacccaa aaagataatt tctatctgat ttgctttaaa 1140

acgttttttt aggatcacaa tgatatcttt gctgtatttg tatagttaga tgctaaatgc 1200

tcattgaaac aatcagctaa tttatgtata gattttccag ctctcaagtt gccatgggcc 1260

ttcatgctat ttaaatattt aagtaattta tgtatttatt agtatattac tgttatttaa 1320

cgtttgtctg ccaggatgta tggaatgttt catactctta tgacctgatc catcaggatc 1380

agtccctatt atgcaaaatg tgaatttaat tttatttgta ctgacaactt ttcaagcaag 1440

gctgcaagta catcagtttt atgacaatca ggaagaatgc agtgttctga taccagtgcc 1500

atcatacact tgtgatggat gggaacgcaa gagatactta catggaaacc tgacaatgca 1560

aacctgttga gaagatccag gagaacaaga tgctagttcc catgtctgtg aagacttcct 1620

ggagatggtg ttgataaagc aatttagggc cacttacact tctaagcaag tttaatcttt 1680

ggatgcctga attttaaaag ggctagaaaa aaatgattga ccagcctggg aaacataaca 1740

agaccccgtc tctacaaaaa aaatttaaaa ttagccaggc gtggtggctc atgcttgtgg 1800

tcccagctgt tcaggaggat gaggcaggag gatctcttga gcccaggagg tcaaggctat 1860

ggtgagccgt gattgtgcca ctgcatacca gcctaggtga cagaatgaga ccctgtctca 1920

aaaaaaaaaa tgattgaaat taaaattcag ctttagcttc catggcagtc ctcaccccca 1980

cctctctaaa agacacagga ggatgacaca gaaacaccgt aagtgtctgg aaggcaaaaa 2040

gatcttaaga ttcaagagag aggacaagta gttatggcta aggacatgaa attgtcagaa 2100

tggcaggtgg cttcttaaca gccctgtgag aagcagacag atgcaaagaa aatctggaat 2160

ccctttctca ttagcatgaa tgaacctgat acacaattat gaccagaaaa tatggctcca 2220

tgaaggtgct acttttaagt aatgtatgtg cgctctgtaa agtgattaca tttgtttcct 2280

gtttgtttat ttatttattt atttttgcat tctgaggctg aactaataaa aactcttctt 2340

tgtaatc 2347

<210> 23

<211> 1498

<212> DNA

<213> Homo sapiens

<400> 23

accaaacctc ttcgaggcac aaggcacaac aggctgctct gggattctct tcagccaatc 60

ttcattgctc aagtgtctga agcagccatg gcagaagtac ctgagctcgc cagtgaaatg 120

atggcttatt acagtggcaa tgaggatgac ttgttctttg aagctgatgg ccctaaacag 180

atgaagtgct ccttccagga cctggacctc tgccctctgg atggcggcat ccagctacga 240

atctccgacc accactacag caagggcttc aggcaggccg cgtcagttgt tgtggccatg 300

gacaagctga ggaagatgct ggttccctgc ccacagacct tccaggagaa tgacctgagc 360

accttctttc ccttcatctt tgaagaagaa cctatcttct tcgacacatg ggataacgag 420

gcttatgtgc acgatgcacc tgtacgatca ctgaactgca cgctccggga ctcacagcaa 480

aaaagcttgg tgatgtctgg tccatatgaa ctgaaagctc tccacctcca gggacaggat 540

atggagcaac aagtggtgtt ctccatgtcc tttgtacaag gagaagaaag taatgacaaa 600

atacctgtgg ccttgggcct caaggaaaag aatctgtacc tgtcctgcgt gttgaaagat 660

gataagccca ctctacagct ggagagtgta gatcccaaaa attacccaaa gaagaagatg 720

gaaaagcgat ttgtcttcaa caagatagaa atcaataaca agctggaatt tgagtctgcc 780

cagttcccca actggtacat cagcacctct caagcagaaa acatgcccgt cttcctggga 840

gggaccaaag gcggccagga tataactgac ttcaccatgc aatttgtgtc ttcctaaaga 900

gagctgtacc cagagagtcc tgtgctgaat gtggactcaa tccctagggc tggcagaaag 960

ggaacagaaa ggtttttgag tacggctata gcctggactt tcctgttgtc tacaccaatg 1020

cccaactgcc tgccttaggg tagtgctaag aggatctcct gtccatcagc caggacagtc 1080

agctctctcc tttcagggcc aatccccagc ccttttgttg agccaggcct ctctcacctc 1140

tcctactcac ttaaagcccg cctgacagaa accacggcca catttggttc taagaaaccc 1200

tctgtcattc gctcccacat tctgatgagc aaccgcttcc ctatttattt atttatttgt 1260

ttgtttgttt tattcattgg tctaatttat tcaaaggggg caagaagtag cagtgtctgt 1320

aaaagagcct agtttttaat agctatggaa tcaattcaat ttggactggt gtgctctctt 1380

taaatcaagt cctttaatta agactgaaaa tatataagct cagattattt aaatgggaat 1440

atttataaat gagcaaatat catactgttc aatggttctg aaataaactt cactgaag 1498

<210> 24

<211> 822

<212> DNA

<213> Homo sapiens

<400> 24

agttccctat cactctcttt aatcactact cacagtaacc tcaactcctg ccacaatgta 60

caggatgcaa ctcctgtctt gcattgcact aagtcttgca cttgtcacaa acagtgcacc 120

tacttcaagt tctacaaaga aaacacagct acaactggag catttactgc tggatttaca 180

gatgattttg aatggaatta ataattacaa gaatcccaaa ctcaccagga tgctcacatt 240

taagttttac atgcccaaga aggccacaga actgaaacat cttcagtgtc tagaagaaga 300

actcaaacct ctggaggaag tgctaaattt agctcaaagc aaaaactttc acttaagacc 360

cagggactta atcagcaata tcaacgtaat agttctggaa ctaaagggat ctgaaacaac 420

attcatgtgt gaatatgctg atgagacagc aaccattgta gaatttctga acagatggat 480

taccttttgt caaagcatca tctcaacact gacttgataa ttaagtgctt cccacttaaa 540

acatatcagg ccttctattt atttaaatat ttaaatttta tatttattgt tgaatgtatg 600

gtttgctacc tattgtaact attattctta atcttaaaac tataaatatg gatcttttat 660

gattcttttt gtaagcccta ggggctctaa aatggtttca cttatttatc ccaaaatatt 720

tattattatg ttgaatgtta aatatagtat ctatgtagat tggttagtaa aactatttaa 780

taaatttgat aaatataaaa aaaaaaaaaa aaaaaaaaaa aa 822

<210> 25

<211> 1049

<212> DNA

<213> Homo sapiens

<400> 25

aaaacaacag gaagcagctt acaaactcgg tgaacaactg agggaaccaa accagagacg 60

cgctgaacag agagaatcag gctcaaagca agtggaagtg ggcagagatt ccaccaggac 120

tggtgcaagg cgcagagcca gccagatttg agaagaaggc aaaaagatgc tggggagcag 180

agctgtaatg ctgctgttgc tgctgccctg gacagctcag ggcagagctg tgcctggggg 240

cagcagccct gcctggactc agtgccagca gctttcacag aagctctgca cactggcctg 300

gagtgcacat ccactagtgg gacacatgga tctaagagaa gagggagatg aagagactac 360

aaatgatgtt ccccatatcc agtgtggaga tggctgtgac ccccaaggac tcagggacaa 420

cagtcagttc tgcttgcaaa ggatccacca gggtctgatt ttttatgaga agctgctagg 480

atcggatatt ttcacagggg agccttctct gctccctgat agccctgtgg gccagcttca 540

tgcctcccta ctgggcctca gccaactcct gcagcctgag ggtcaccact gggagactca 600

gcagattcca agcctcagtc ccagccagcc atggcagcgt ctccttctcc gcttcaaaat 660

ccttcgcagc ctccaggcct ttgtggctgt agccgcccgg gtctttgccc atggagcagc 720

aaccctgagt ccctaaaggc agcagctcaa ggatggcact cagatctcca tggcccagca 780

aggccaagat aaatctacca ccccaggcac ctgtgagcca acaggttaat tagtccatta 840

attttagtgg gacctgcata tgttgaaaat taccaatact gactgacatg tgatgctgac 900

ctatgataag gttgagtatt tattagatgg gaagggaaat ttggggatta tttatcctcc 960

tggggacagt ttggggagga ttatttattg tatttatatt gaattatgta cttttttcaa 1020

taaagtctta tttttgtggc taaaaaaaa 1049

<210> 26

<211> 1201

<212> DNA

<213> Homo sapiens

<400> 26

aatattagag tctcaacccc caataaatat aggactggag atgtctgagg ctcattctgc 60

cctcgagccc accgggaacg aaagagaagc tctatctccc ctccaggagc ccagctatga 120

actccttctc cacaagcgcc ttcggtccag ttgccttctc cctggggctg ctcctggtgt 180

tgcctgctgc cttccctgcc ccagtacccc caggagaaga ttccaaagat gtagccgccc 240

cacacagaca gccactcacc tcttcagaac gaattgacaa acaaattcgg tacatcctcg 300

acggcatctc agccctgaga aaggagacat gtaacaagag taacatgtgt gaaagcagca 360

aagaggcact ggcagaaaac aacctgaacc ttccaaagat ggctgaaaaa gatggatgct 420

tccaatctgg attcaatgag gagacttgcc tggtgaaaat catcactggt cttttggagt 480

ttgaggtata cctagagtac ctccagaaca gatttgagag tagtgaggaa caagccagag 540

ctgtgcagat gagtacaaaa gtcctgatcc agttcctgca gaaaaaggca aagaatctag 600

atgcaataac cacccctgac ccaaccacaa atgccagcct gctgacgaag ctgcaggcac 660

agaaccagtg gctgcaggac atgacaactc atctcattct gcgcagcttt aaggagttcc 720

tgcagtccag cctgagggct cttcggcaaa tgtagcatgg gcacctcaga ttgttgttgt 780

taatgggcat tccttcttct ggtcagaaac ctgtccactg ggcacagaac ttatgttgtt 840

ctctatggag aactaaaagt atgagcgtta ggacactatt ttaattattt ttaatttatt 900

aatatttaaa tatgtgaagc tgagttaatt tatgtaagtc atatttatat ttttaagaag 960

taccacttga aacattttat gtattagttt tgaaataata atggaaagtg gctatgcagt 1020

ttgaatatcc tttgtttcag agccagatca tttcttggaa agtgtaggct tacctcaaat 1080

aaatggctaa cttatacata tttttaaaga aatatttata ttgtatttat ataatgtata 1140

aatggttttt ataccaataa atggcatttt aaaaaattca gcaaaaaaaa aaaaaaaaaa 1200

a 1201

<210> 27

<211> 1718

<212> DNA

<213> Homo sapiens

<400> 27

gagggtgcat aagttctcta gtagggtgat gatataaaaa gccaccggag cactccataa 60

ggcacaaact ttcagagaca gcagagcaca caagcttcta ggacaagagc caggaagaaa 120

ccaccggaag gaaccatctc actgtgtgta aacatgactt ccaagctggc cgtggctctc 180

ttggcagcct tcctgatttc tgcagctctg tgtgaaggtg cagttttgcc aaggagtgct 240

aaagaactta gatgtcagtg cataaagaca tactccaaac ctttccaccc caaatttatc 300

aaagaactga gagtgattga gagtggacca cactgcgcca acacagaaat tattgtaaag 360

ctttctgatg gaagagagct ctgtctggac cccaaggaaa actgggtgca gagggttgtg 420

gagaagtttt tgaagagggc tgagaattca taaaaaaatt cattctctgt ggtatccaag 480

aatcagtgaa gatgccagtg aaacttcaag caaatctact tcaacacttc atgtattgtg 540

tgggtctgtt gtagggttgc cagatgcaat acaagattcc tggttaaatt tgaatttcag 600

taaacaatga atagtttttc attgtaccat gaaatatcca gaacatactt atatgtaaag 660

tattatttat ttgaatctac aaaaaacaac aaataatttt taaatataag gattttccta 720

gatattgcac gggagaatat acaaatagca aaattgaggc caagggccaa gagaatatcc 780

gaactttaat ttcaggaatt gaatgggttt gctagaatgt gatatttgaa gcatcacata 840

aaaatgatgg gacaataaat tttgccataa agtcaaattt agctggaaat cctggatttt 900

tttctgttaa atctggcaac cctagtctgc tagccaggat ccacaagtcc ttgttccact 960

gtgccttggt ttctccttta tttctaagtg gaaaaagtat tagccaccat cttacctcac 1020

agtgatgttg tgaggacatg tggaagcact ttaagttttt tcatcataac ataaattatt 1080

ttcaagtgta acttattaac ctatttatta tttatgtatt tatttaagca tcaaatattt 1140

gtgcaagaat ttggaaaaat agaagatgaa tcattgattg aatagttata aagatgttat 1200

agtaaattta ttttatttta gatattaaat gatgttttat tagataaatt tcaatcaggg 1260

tttttagatt aaacaaacaa acaattgggt acccagttaa attttcattt cagataaaca 1320

acaaataatt ttttagtata agtacattat tgtttatctg aaattttaat tgaactaaca 1380

atcctagttt gatactccca gtcttgtcat tgccagctgt gttggtagtg ctgtgttgaa 1440

ttacggaata atgagttaga actattaaaa cagccaaaac tccacagtca atattagtaa 1500

tttcttgctg gttgaaactt gtttattatg tacaaataga ttcttataat attatttaaa 1560

tgactgcatt tttaaataca aggctttata tttttaactt taagatgttt ttatgtgctc 1620

tccaaatttt ttttactgtt tctgattgta tggaaatata aaagtaaata tgaaacattt 1680

aaaatataat ttgttgtcaa agtaaaaaaa aaaaaaaa 1718

<210> 28

<211> 3567

<212> DNA

<213> Homo sapiens

<400> 28

agagctcgcc actccttagt cgaggcaaga cgtgcgcccg agccccgccg aaccgaggcc 60

acccggagcc gtgcccagtc cacgccggcc gtgcccggcg gccttaagaa cccggcaacc 120

tctgccttct tccctcttcc actcggagtc gcgctccgcg cgccctcact gcagcccctg 180

cgtcgccggg accctcgcgc gcgaccgccg aatcgctcct gcagcagagc caacatgccc 240

atcactcgga tgcgcatgag accctggcta gagatgcaga ttaattccaa ccaaatcccg 300

gggctcatct ggattaataa agaggagatg atcttccaga tcccatggaa gcatgctgcc 360

aagcatggct gggacatcaa caaggatgcc tgtttgttcc ggagctgggc cattcacaca 420

ggccgataca aagcagggga aaaggagcca gatcccaaga cgtggaaggc caactttcgc 480

tgtgccatga actccctgcc agatatcgag gaggtgaaag accagagcag gaacaagggc 540

agctcagctg tgcgagtgta ccggatgctt ccacctctca ccaagaacca gagaaaagaa 600

agaaagtcga agtccagccg agatgctaag agcaaggcca agaggaagtc atgtggggat 660

tccagccctg ataccttctc tgatggactc agcagctcca ctctgcctga tgaccacagc 720

agctacacag ttccaggcta catgcaggac ttggaggtgg agcaggccct gactccagca 780

ctgtcgccat gtgctgtcag cagcactctc cccgactggc acatcccagt ggaagttgtg 840

ccggacagca ccagtgatct gtacaacttc caggtgtcac ccatgccctc cacctctgaa 900

gctacaacag atgaggatga ggaagggaaa ttacctgagg acatcatgaa gctcttggag 960

cagtcggagt ggcagccaac aaacgtggat gggaaggggt acctactcaa tgaacctgga 1020

gtccagccca cctctgtcta tggagacttt agctgtaagg aggagccaga aattgacagc 1080

ccaggggggg atattgggct gagtctacag cgtgtcttca cagatctgaa gaacatggat 1140

gccacctggc tggacagcct gctgacccca gtccggttgc cctccatcca ggccattccc 1200

tgtgcaccgt agcagggccc ctgggcccct cttattcctc taggcaagca ggacctggca 1260

tcatggtgga tatggtgcag agaagctgga cttctgtggg cccctcaaca gccaagtgtg 1320

accccactgc caagtgggga tggggcctcc ctccttgggt cattgacctc tcagggcctg 1380

gcaggccagt gtctgggttt ttcttgtggt gtaaagctgg ccctgcctcc tgggaagatg 1440

aggttctgag accagtgtat caggtcaggg acttggacag gagtcagtgt ctggcttttt 1500

cctctgagcc cagctgcctg gagagggtct cgctgtcact ggctggctcc taggggaaca 1560

gaccagtgac cccagaaaag cataacacca atcccagggc tggctctgca ctaagagaaa 1620

attgcactaa atgaatctcg ttcccaaaga actaccccct tttcagctga gccctgggga 1680

ctgttccaaa gccagtgaaa tgtgaaggaa agtggggtcc ttcggggcga tgctccctca 1740

gcctcagagg agctctaccc tgctccctgc tttggctgag gggcttggga aaaaaacttg 1800

gcactttttc gtgtggatct tgccacattt ctgatcagag gtgtacacta acatttcccc 1860

cgagctcttg gcctttgcat ttatttatac agtgccttgc tcggcgccca ccaccccctc 1920

aagccccagc agccctcaac aggcccaggg agggaagtgt gagcgccttg gtatgactta 1980

aaattggaaa tgtcatctaa ccattaagtc atgtgtgaac acataaggac gtgtgtaaat 2040

atgtacattt gtctttttat aaaaagtaaa ttgtttataa ggggtgtggc ctttttagag 2100

agaaatttaa cttgtagatg attttacttt ttatggaaac actgatggac ttattattgg 2160

catcccgcct gaacttgact ttggggtgaa cagggacatg catctattat aaaatccttt 2220

cggccaggcg cggtggctca cacctgtaat cccagcactt tgggaggccg agatgggtgg 2280

atcacctgag gtcaggagtt cgagaccagc ctggtgaaac tccatttcta ctaaaaatgc 2340

aaaaattagc tgggcgtggt tgcgggtgct tgtaatccca gctactcagg aggctgaggc 2400

aagagaatcg cttgaacctg ggaggtggag gttgcagtga gccgagaaca tgccattgca 2460

ctccagcccg ggcaccaaaa aaaaaaaaaa aaaaaaaaac ctttcatttg gccgggcatg 2520

gtggcttatg cctgtaatcc tggcactttg ggaggccaag gtgggcagat cacctgaggt 2580

caggagtttg agaccagcct ggccaacatg gtgaaacctc atctctacta aaaatacaaa 2640

aattaggccg ggcacggtgg ctcacgcctg taatcccagc actttgggag gcagaggcgg 2700

gcggatcacg aggtcaggag atcaagacca tcctggctaa cacggtgaaa ccccgtctct 2760

actaaaaata taaaaaatta gccgggccta gtggcgggtg cctgtagtcc cagctactcg 2820

ggaggctgag gcaggagaat ggcatgaacc ccggaggcag agcttgcagt gagccgagat 2880

tgcaccactg cactacagcc tgggcgacag agcgagactc cgtctcaaaa aaaaaaaaaa 2940

aaattagccg ggcctggtgg cgggcgcctg taatcccagc tactgtggag gctgaagcac 3000

aagaatcact tgaacccggg agatggaggt tgcagtgagc tgagactgtg ccactgcact 3060

ccagcctggg tgacaagagt gagactttgt ctcaaaaaaa aaaaaatcct tttgtttatg 3120

ttcacataga caatggcaga aggaggggac attcctgtca taggaacatg cttatataaa 3180

catagtcacc tgtccttgac tatcaccagg gctgtcagtt gattctgggc tcctggggcc 3240

caaggagtgt taagttttga ggcatgtgcc ataggtgatg tgtcctgcta acacacagat 3300

gctgctccaa aaagtcagtt gatatgacac agtcacagac agaacagtca gcagcccaag 3360

aaaggtcctc acggctgctg tgctgggtag cacttgccat ccagtttcta gagtgatgaa 3420

atgctctgtc tgtaccgttc aatacagtag gcactggcac tagccacatg tgccagctaa 3480

gcacttgaaa tgtggccagt gcaataagga attgaacttt taattgcatt taataaactg 3540

tatgtaaata gtcaaaaaaa aaaaaaa 3567

<210> 29

<211> 2387

<212> DNA

<213> Homo sapiens

<400> 29

agacacctct gccctcacca tgagcctctg gcagcccctg gtcctggtgc tcctggtgct 60

gggctgctgc tttgctgccc ccagacagcg ccagtccacc cttgtgctct tccctggaga 120

cctgagaacc aatctcaccg acaggcagct ggcagaggaa tacctgtacc gctatggtta 180

cactcgggtg gcagagatgc gtggagagtc gaaatctctg gggcctgcgc tgctgcttct 240

ccagaagcaa ctgtccctgc ccgagaccgg tgagctggat agcgccacgc tgaaggccat 300

gcgaacccca cggtgcgggg tcccagacct gggcagattc caaacctttg agggcgacct 360

caagtggcac caccacaaca tcacctattg gatccaaaac tactcggaag acttgccgcg 420

ggcggtgatt gacgacgcct ttgcccgcgc cttcgcactg tggagcgcgg tgacgccgct 480

caccttcact cgcgtgtaca gccgggacgc agacatcgtc atccagtttg gtgtcgcgga 540

gcacggagac gggtatccct tcgacgggaa ggacgggctc ctggcacacg cctttcctcc 600

tggccccggc attcagggag acgcccattt cgacgatgac gagttgtggt ccctgggcaa 660

gggcgtcgtg gttccaactc ggtttggaaa cgcagatggc gcggcctgcc acttcccctt 720

catcttcgag ggccgctcct actctgcctg caccaccgac ggtcgctccg acggcttgcc 780

ctggtgcagt accacggcca actacgacac cgacgaccgg tttggcttct gccccagcga 840

gagactctac acccaggacg gcaatgctga tgggaaaccc tgccagtttc cattcatctt 900

ccaaggccaa tcctactccg cctgcaccac ggacggtcgc tccgacggct accgctggtg 960

cgccaccacc gccaactacg accgggacaa gctcttcggc ttctgcccga cccgagctga 1020

ctcgacggtg atggggggca actcggcggg ggagctgtgc gtcttcccct tcactttcct 1080

gggtaaggag tactcgacct gtaccagcga gggccgcgga gatgggcgcc tctggtgcgc 1140

taccacctcg aactttgaca gcgacaagaa gtggggcttc tgcccggacc aaggatacag 1200

tttgttcctc gtggcggcgc atgagttcgg ccacgcgctg ggcttagatc attcctcagt 1260

gccggaggcg ctcatgtacc ctatgtaccg cttcactgag gggcccccct tgcataagga 1320

cgacgtgaat ggcatccggc acctctatgg tcctcgccct gaacctgagc cacggcctcc 1380

aaccaccacc acaccgcagc ccacggctcc cccgacggtc tgccccaccg gaccccccac 1440

tgtccacccc tcagagcgcc ccacagctgg ccccacaggt cccccctcag ctggccccac 1500

aggtcccccc actgctggcc cttctacggc cactactgtg cctttgagtc cggtggacga 1560

tgcctgcaac gtgaacatct tcgacgccat cgcggagatt gggaaccagc tgtatttgtt 1620

caaggatggg aagtactggc gattctctga gggcaggggg agccggccgc agggcccctt 1680

ccttatcgcc gacaagtggc ccgcgctgcc ccgcaagctg gactcggtct ttgaggagcg 1740

gctctccaag aagcttttct tcttctctgg gcgccaggtg tgggtgtaca caggcgcgtc 1800

ggtgctgggc ccgaggcgtc tggacaagct gggcctggga gccgacgtgg cccaggtgac 1860

cggggccctc cggagtggca gggggaagat gctgctgttc agcgggcggc gcctctggag 1920

gttcgacgtg aaggcgcaga tggtggatcc ccggagcgcc agcgaggtgg accggatgtt 1980

ccccggggtg cctttggaca cgcacgacgt cttccagtac cgagagaaag cctatttctg 2040

ccaggaccgc ttctactggc gcgtgagttc ccggagtgag ttgaaccagg tggaccaagt 2100

gggctacgtg acctatgaca tcctgcagtg ccctgaggac tagggctccc gtcctgcttt 2160

ggcagtgcca tgtaaatccc cactgggacc aaccctgggg aaggagccag tttgccggat 2220

acaaactggt attctgttct ggaggaaagg gaggagtgga ggtgggctgg gccctctctt 2280

ctcacctttg ttttttgttg gagtgtttct aataaacttg gattctctaa cctttaaaaa 2340

aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaa 2387

<210> 30

<211> 2379

<212> DNA

<213> Homo sapiens

<400> 30

gacccccgag ctgtgctgct cgcggccgcc accgccgggc cccggccgtc cctggctccc 60

ctcctgcctc gagaagggca gggcttctca gaggcttggc gggaaaaaga acggagggag 120

ggatcgcgct gagtataaaa gccggttttc ggggctttat ctaactcgct gtagtaattc 180

cagcgagagg cagagggagc gagcgggcgg ccggctaggg tggaagagcc gggcgagcag 240

agctgcgctg cgggcgtcct gggaagggag atccggagcg aatagggggc ttcgcctctg 300

gcccagccct cccgctgatc ccccagccag cggtccgcaa cccttgccgc atccacgaaa 360

ctttgcccat agcagcgggc gggcactttg cactggaact tacaacaccc gagcaaggac 420

gcgactctcc cgacgcgggg aggctattct gcccatttgg ggacacttcc ccgccgctgc 480

caggacccgc ttctctgaaa ggctctcctt gcagctgctt agacgctgga tttttttcgg 540

gtagtggaaa accagcagcc tcccgcgacg atgcccctca acgttagctt caccaacagg 600

aactatgacc tcgactacga ctcggtgcag ccgtatttct actgcgacga ggaggagaac 660

ttctaccagc agcagcagca gagcgagctg cagcccccgg cgcccagcga ggatatctgg 720

aagaaattcg agctgctgcc caccccgccc ctgtccccta gccgccgctc cgggctctgc 780

tcgccctcct acgttgcggt cacacccttc tcccttcggg gagacaacga cggcggtggc 840

gggagcttct ccacggccga ccagctggag atggtgaccg agctgctggg aggagacatg 900

gtgaaccaga gtttcatctg cgacccggac gacgagacct tcatcaaaaa catcatcatc 960

caggactgta tgtggagcgg cttctcggcc gccgccaagc tcgtctcaga gaagctggcc 1020

tcctaccagg ctgcgcgcaa agacagcggc agcccgaacc ccgcccgcgg ccacagcgtc 1080

tgctccacct ccagcttgta cctgcaggat ctgagcgccg ccgcctcaga gtgcatcgac 1140

ccctcggtgg tcttccccta ccctctcaac gacagcagct cgcccaagtc ctgcgcctcg 1200

caagactcca gcgccttctc tccgtcctcg gattctctgc tctcctcgac ggagtcctcc 1260

ccgcagggca gccccgagcc cctggtgctc catgaggaga caccgcccac caccagcagc 1320

gactctgagg aggaacaaga agatgaggaa gaaatcgatg ttgtttctgt ggaaaagagg 1380

caggctcctg gcaaaaggtc agagtctgga tcaccttctg ctggaggcca cagcaaacct 1440

cctcacagcc cactggtcct caagaggtgc cacgtctcca cacatcagca caactacgca 1500

gcgcctccct ccactcggaa ggactatcct gctgccaaga gggtcaagtt ggacagtgtc 1560

agagtcctga gacagatcag caacaaccga aaatgcacca gccccaggtc ctcggacacc 1620

gaggagaatg tcaagaggcg aacacacaac gtcttggagc gccagaggag gaacgagcta 1680

aaacggagct tttttgccct gcgtgaccag atcccggagt tggaaaacaa tgaaaaggcc 1740

cccaaggtag ttatccttaa aaaagccaca gcatacatcc tgtccgtcca agcagaggag 1800

caaaagctca tttctgaaga ggacttgttg cggaaacgac gagaacagtt gaaacacaaa 1860

cttgaacagc tacggaactc ttgtgcgtaa ggaaaagtaa ggaaaacgat tccttctaac 1920

agaaatgtcc tgagcaatca cctatgaact tgtttcaaat gcatgatcaa atgcaacctc 1980

acaaccttgg ctgagtcttg agactgaaag atttagccat aatgtaaact gcctcaaatt 2040

ggactttggg cataaaagaa cttttttatg cttaccatct tttttttttc tttaacagat 2100

ttgtatttaa gaattgtttt taaaaaattt taagatttac acaatgtttc tctgtaaata 2160

ttgccattaa atgtaaataa ctttaataaa acgtttatag cagttacaca gaatttcaat 2220

cctagtatat agtacctagt attataggta ctataaaccc taattttttt tatttaagta 2280

cattttgctt tttaaagttg atttttttct attgttttta gaaaaaataa aataactggc 2340

aaatatatca ttgagccaaa tcttaaaaaa aaaaaaaaa 2379

<210> 31

<211> 3125

<212> DNA

<213> Homo sapiens

<400> 31

ccgcaaccag agccgccgcc acggtgagtg gctggattca gacccctggg tggccgggac 60

aagagaaaag agggaggagg gcctttagcg gacagcgcct ggggctggag agcagcagct 120

gcacacagcc ggaaagggcg cgcaggcgac gacactcgga tccacgtcga caccgttgta 180

caaagatacg cggacccgcg ggcgtctaaa attctgggaa gcagaacctg gccggagcca 240

ctagacagag ccgggcctag cccagagaca tggagagttg ctacaaccca ggtctggatg 300

gtattattga atatgatgat ttcaaattga actcctccat tgtggaaccc aaggagccag 360

ccccagaaac agctgatggc ccctacctgg tgatcgtgga acagcctaag cagagaggct 420

tccgatttcg atatggctgt gaaggcccct cccatggagg actgcccggt gcctccagtg 480

agaagggccg aaagacctat cccactgtca agatctgtaa ctacgaggga ccagccaaga 540

tcgaggtgga cctggtaaca cacagtgacc cacctcgtgc tcatgcccac agtctggtgg 600

gcaagcaatg ctcggagctg gggatctgcg ccgtttctgt ggggcccaag gacatgactg 660

cccaatttaa caacctgggt gtcctgcatg tgactaagaa gaacatgatg gggactatga 720

tacaaaaact tcagaggcag cggctccgct ctaggcccca gggccttacg gaggccgagc 780

agcgggagct ggagcaagag gccaaagaac tgaagaaggt gatggatctg agtatagtgc 840

ggctgcgctt ctctgccttc cttagagcca gtgatggctc cttctccctg cccctgaagc 900

cagtcatctc ccagcccatc catgacagca aatctccggg ggcatcaaac ctgaagattt 960

ctcgaatgga caagacagca ggctctgtgc ggggtggaga tgaagtttat ctgctttgtg 1020

acaaggtgca gaaagatgac attgaggttc ggttctatga ggatgatgag aatggatggc 1080

aggcctttgg ggacttctct cccacagatg tgcataaaca gtatgccatt gtgttccgga 1140

caccccccta tcacaagatg aagattgagc ggcctgtaac agtgtttctg caactgaaac 1200

gcaagcgagg aggggacgtg tctgattcca aacagttcac ctattaccct ctggtggaag 1260

acaaggaaga ggtgcagcgg aagcggagga aggccttgcc caccttctcc cagcccttcg 1320

ggggtggctc ccacatgggt ggaggctctg ggggtgcagc cgggggctac ggaggagctg 1380

gaggaggtgg cagcctcggt ttcttcccct cctccctggc ctacagcccc taccagtccg 1440

gcgcgggccc catgggctgc tacccgggag gcgggggcgg ggcgcagatg gccgccacgg 1500

tgcccagcag ggactccggg gaggaagccg cggagccgag cgccccctcc aggacccccc 1560

agtgcgagcc gcaggccccg gagatgctgc agcgagctcg agagtacaac gcgcgcctgt 1620

tcggcctggc gcagcgcagc gcccgagccc tactcgacta cggcgtcacc gcggacgcgc 1680

gcgcgctgct ggcgggacag cgccacctgc tgacggcgca ggacgagaac ggagacacac 1740

cactgcacct agccatcatc cacgggcaga ccagtgtcat tgagcagata gtctatgtca 1800

tccaccacgc ccaggacctc ggcgttgtca acctcaccaa ccacctgcac cagacgcccc 1860

tgcacctggc ggtgatcacg gggcagacga gtgtggtgag ctttctgctg cgggtaggtg 1920

cagacccagc tctgctggat cggcatggag actcagccat gcatctggcg ctgcgggcag 1980

gcgctggtgc tcctgagctg ctgcgtgcac tgcttcagag tggagctcct gctgtgcccc 2040

agctgttgca tatgcctgac tttgagggac tgtatccagt acacctggcg gtccgagccc 2100

gaagccctga gtgcctggat ctgctggtgg acagtggggc tgaagtggag gccacagagc 2160

ggcagggggg acgaacagcc ttgcatctag ccacagagat ggaggagctg gggttggtca 2220

cccatctggt caccaagctc cgggccaacg tgaacgctcg cacctttgcg ggaaacacac 2280

ccctgcacct ggcagctgga ctggggtacc cgaccctcac ccgcctcctt ctgaaggctg 2340

gtgctgacat ccatgctgaa aacgaggagc ccctgtgccc actgccttca ccccctacct 2400

ctgatagcga ctcggactct gaagggcctg agaaggacac ccgaagcagc ttccggggcc 2460

acacgcctct tgacctcact tgcagcacca aggtgaagac cttgctgcta aatgctgctc 2520

agaacaccat ggagccaccc ctgaccccgc ccagcccagc agggccggga ctgtcacttg 2580

gtgatacagc tctgcagaac ctggagcagc tgctagacgg gccagaagcc cagggcagct 2640

gggcagagct ggcagagcgt ctggggctgc gcagcctggt agacacgtac cgacagacaa 2700

cctcacccag tggcagcctc ctgcgcagct acgagctggc tggcggggac ctggcaggtc 2760

tactggaggc cctgtctgac atgggcctag aggagggagt gaggctgctg aggggtccag 2820

aaacccgaga caagctgccc agcacagcag aggtgaagga agacagtgcg tacgggagcc 2880

agtcagtgga gcaggaggca gagaagctgg gcccaccccc tgagccacca ggagggctct 2940

gccacgggca cccccagcct caggtgcact gacctgctgc ctgcccccag cccccttccc 3000

ggaccccctg tacagcgtcc ccacctattt caaatcttat ttaacacccc acacccaccc 3060

ctcagttggg acaaataaag gattctcatg ggaaggggag gacccctcct tcccaactta 3120

tggca 3125

<210> 32

<211> 1579

<212> DNA

<213> Homo sapiens

<400> 32

agcccacagc agtccgtgcc gccgtcccgc ccgccagcgc cccagcgagg aagcagcgcg 60

cagcccgcgg cccagcgcac ccgcagcagc gcccgcagct cgtccgcgcc atgttccagg 120

cggccgagcg cccccaggag tgggccatgg agggcccccg cgacgggctg aagaaggagc 180

ggctactgga cgaccgccac gacagcggcc tggactccat gaaagacgag gagtacgagc 240

agatggtcaa ggagctgcag gagatccgcc tcgagccgca ggaggtgccg cgcggctcgg 300

agccctggaa gcagcagctc accgaggacg gggactcgtt cctgcacttg gccatcatcc 360

atgaagaaaa ggcactgacc atggaagtga tccgccaggt gaagggagac ctggccttcc 420

tcaacttcca gaacaacctg cagcagactc cactccactt ggctgtgatc accaaccagc 480

cagaaattgc tgaggcactt ctgggagctg gctgtgatcc tgagctccga gactttcgag 540

gaaatacccc cctacacctt gcctgtgagc agggctgcct ggccagcgtg ggagtcctga 600

ctcagtcctg caccaccccg cacctccact ccatcctgaa ggctaccaac tacaatggcc 660

acacgtgtct acacttagcc tctatccatg gctacctggg catcgtggag cttttggtgt 720

ccttgggtgc tgatgtcaat gctcaggagc cctgtaatgg ccggactgcc cttcacctcg 780

cagtggacct gcaaaatcct gacctggtgt cactcctgtt gaagtgtggg gctgatgtca 840

acagagttac ctaccagggc tattctccct accagctcac ctggggccgc ccaagcaccc 900

ggatacagca gcagctgggc cagctgacac tagaaaacct tcagatgctg ccagagagtg 960

aggatgagga gagctatgac acagagtcag agttcacgga gttcacagag gacgagctgc 1020

cctatgatga ctgtgtgttt ggaggccagc gtctgacgtt atgagcgcaa aggggctgaa 1080

agaacatgga cttgtatatt tgtacaaaaa aaaagtttta tttttctaaa aaaagaaaaa 1140

agaagaaaaa atttaaaggg tgtacttata tccacactgc acactgcctg gcccaaaacg 1200

tcttattgtg gtaggatcag ccctcatttt gttgcttttg tgaacttttt gtaggggacg 1260

agaaagatca ttgaaattct gagaaaactt cttttaaacc tcacctttgt ggggtttttg 1320

gagaaggtta tcaaaaattt catggaagga ccacatttta tatttattgt gcttcgagtg 1380

actgacccca gtggtatcct gtgacatgta acagccagga gtgttaagcg ttcagtgatg 1440

tggggtgaaa agttactacc tgtcaaggtt tgtgttaccc tcctgtaaat ggtgtacata 1500

atgtattgtt ggtaattatt ttggtacttt tatgatgtat atttattaaa cagattttta 1560

caaatgaaaa aaaaaaaaa 1579

<210> 33

<211> 2581

<212> DNA

<213> Homo sapiens

<400> 33

aatgaatgaa tgaatgaatg agtgaatgaa tcaacgaagg agtgagtcaa ggcccgggaa 60

ccacagactc caagcctacg cagagcccgg gaagggggat tccggagggg cggggcctct 120

ttccggaagc gcccgccggg ggcggggagg gggcggggcc atccgcgtga ggcgaccctg 180

ttggtccgga ggggcggggc gaggaggagg acccgcttgg gcggttcggc tgcccacagt 240

aaccgctggg tggacctggc cagcgctccg aaccttgtcc tcgctgcgcg ccggcccctc 300

ggagccccac agcccgggaa ggaggccgcc gcgggccggg cgcccgctct gccaagcgga 360

cccgcaaccc ggaaaggcgg cgcggcggag cctggagccg gatcctgctc agaccgggcc 420

ccggccggcc agagccgcgg gcatgtcgga ggcgcggaag gggccggacg aggcggagga 480

gagccagtac gactctggca ttgagtctct gcgctctctg cgctccctac ccgagtccac 540

ctcggctcca gcctccgggc cctcggacgg cagcccccag ccctgcaccc atcctccggg 600

acccgtcaag gaaccacagg agaaggaaga cgcggatggg gagcgggctg attccaccta 660

tggctcctcc tcgctcacct acaccctgtc cttgctgggg ggccccgagg ctgaggaccc 720

ggccccacgc ctgccactcc cccacgtggg ggcgctgagc cctcagcagc tggaagcact 780

cacttacatc tccgaggacg gagacacgct ggtccacctg gcagtgattc atgaggcccc 840

agcggtgctg ctctgttgcc tggctttgct gccccaggag gtcctggaca ttcaaaataa 900

cctttaccag acagcactcc atctggctgt acatctggac caaccgggcg cagttcgggc 960

actggtgctg aagggggcca gccgggcact acaggaccgg catggtgaca cagcccttca 1020

tgtggcctgc cagcgccagc acttggcctg tgcccgctgc ctgctggaag ggcggccaga 1080

gccaggcaga ggaacatctc actctctgga cctccagctg caaaactggc aaggtctggc 1140

ttgtctccac attgccaccc ttcagaagaa ccaaccactc atggaattgc tgcttcggaa 1200

tggagctgac attgatgtgc aggagggcac cagtggtaag acagcgctgc acctggctgt 1260

ggaaacccaa gagcggggcc tggtacagtt cctgctccag gctggtgccc aggtagatgc 1320

ccgcatgctg aacgggtgca cacccctgca cctggcagct ggccggggtc tcatgggcat 1380

ctcatccact ctgtgcaagg cgggtgctga ctccctgctg cggaatgtgg aggatgagac 1440

gccccaggac ctgactgagg aatcccttgt ccttttgccc tttgatgacc tgaagatctc 1500

agggaaactg ctgctgtgta ccgactgaag ccaggcaggg tctgggatcc tcagggctcc 1560

acctctccat ctggaagccg gagccataac tgctgcagtt tgggcccagg ctatgtgctc 1620

ttctggtgcc ctagggactg ctgtggccag agcctggggc cagccagtac agtcctgagc 1680

cgaggaggag ggactgcaag tggaagagag ccagtctgga aggaagagct ttccaggtgg 1740

acagggcttc ttggaagacc cccaaagccc caggtatcct gggtgaagcc tgtttgcctc 1800

tcttgaaaat ggcaggtgct cttgttttac ccatgttggg tcagcctgaa actgccaacc 1860

agtaggaagc atggactctc ctgagtgaga agagactgaa ataggagcaa gcagaaccct 1920

gagaggtgtc ccatcttatt gctgttgagg accctgaaac accgttgttt aaagacttca 1980

cacagaaggc tctgaactga gccactgggg aagggaagtt tcagtaacat gacactaaaa 2040

tggcagagac gttaaaaaaa gtttttccct tctagagctg ttttgcgcgc atgcatgtct 2100

gtgtgcattg gggcttttta gacaggcctg ccctgtgact ttgtggtaga ggcagagaga 2160

aggaaattgt cccctgagca cggtagggcc ttgctgggtg gggtcagagg ccagtagttc 2220

caggcctttc tctgtgtcca gcacagaccc ttgtccttgc tgtggaaatg atgagggatg 2280

gagggacaag aggaagaatg agaggacaca cgccctggag ccctcaccac tgccctgggg 2340

gttgccatct ggaggagcct ggggataagg gtaacccagg gaggctgggc acgagggagc 2400

tgactccacg tttttccccc cgttcctcac cttcgagggc cctgctaggt cacccctatg 2460

ctggcatgaa gagcatgggg caataaacca gcacagtctc tgaccacttg gagcgtctca 2520

tccagtgaga gagacagccg ttaaaagcat aaacatccaa ataaagatgc ctttccaagt 2580

t 2581

<210> 34

<211> 4206

<212> DNA

<213> Homo sapiens

<400> 34

ataactttgt agcgagtcga aaactgaggc tccggccgca gagaactcag cctcattcct 60

gctttaaaat ctctcggcca cctttgatga ggggactggg cagttctaga cagtcccgaa 120

gttctcaagg cacaggtctc ttcctggttt gactgtcctt accccgggga ggcagtgcag 180

ccagctgcaa gccccacagt gaagaacatc tgagctcaaa tccagataag tgacataagt 240

gacctgcttt gtaaagccat agagatggcc tgtccttgga aatttctgtt caagaccaaa 300

ttccaccagt atgcaatgaa tggggaaaaa gacatcaaca acaatgtgga gaaagccccc 360

tgtgccacct ccagtccagt gacacaggat gaccttcagt atcacaacct cagcaagcag 420

cagaatgagt ccccgcagcc cctcgtggag acgggaaaga agtctccaga atctctggtc 480

aagctggatg caaccccatt gtcctcccca cggcatgtga ggatcaaaaa ctggggcagc 540

gggatgactt tccaagacac acttcaccat aaggccaaag ggattttaac ttgcaggtcc 600

aaatcttgcc tggggtccat tatgactccc aaaagtttga ccagaggacc cagggacaag 660

cctacccctc cagatgagct tctacctcaa gctatcgaat ttgtcaacca atattacggc 720

tccttcaaag aggcaaaaat agaggaacat ctggccaggg tggaagcggt aacaaaggag 780

atagaaacaa caggaaccta ccaactgacg ggagatgagc tcatcttcgc caccaagcag 840

gcctggcgca atgccccacg ctgcattggg aggatccagt ggtccaacct gcaggtcttc 900

gatgcccgca gctgttccac tgcccgggaa atgtttgaac acatctgcag acacgtgcgt 960

tactccacca acaatggcaa catcaggtcg gccatcaccg tgttccccca gcggagtgat 1020

ggcaagcacg acttccgggt gtggaatgct cagctcatcc gctatgctgg ctaccagatg 1080

ccagatggca gcatcagagg ggaccctgcc aacgtggaat tcactcagct gtgcatcgac 1140

ctgggctgga agcccaagta cggccgcttc gatgtggtcc ccctggtcct gcaggccaat 1200

ggccgtgacc ctgagctctt cgaaatccca cctgaccttg tgcttgaggt ggccatggaa 1260

catcccaaat acgagtggtt tcgggaactg gagctaaagt ggtacgccct gcctgcagtg 1320

gccaacatgc tgcttgaggt gggcggcctg gagttcccag ggtgcccctt caatggctgg 1380

tacatgggca cagagatcgg agtccgggac ttctgtgacg tccagcgcta caacatcctg 1440

gaggaagtgg gcaggagaat gggcctggaa acgcacaagc tggcctcgct ctggaaagac 1500

caggctgtcg ttgagatcaa cattgctgtg ctccatagtt tccagaagca gaatgtgacc 1560

atcatggacc accactcggc tgcagaatcc ttcatgaagt acatgcagaa tgaataccgg 1620

tcccgtgggg gctgcccggc agactggatt tggctggtcc ctcccatgtc tgggagcatc 1680

acccccgtgt ttcaccagga gatgctgaac tacgtcctgt cccctttcta ctactatcag 1740

gtagaggcct ggaaaaccca tgtctggcag gacgagaagc ggagacccaa gagaagagag 1800

attccattga aagtcttggt caaagctgtg ctctttgcct gtatgctgat gcgcaagaca 1860

atggcgtccc gagtcagagt caccatcctc tttgcgacag agacaggaaa atcagaggcg 1920

ctggcctggg acctgggggc cttattcagc tgtgccttca accccaaggt tgtctgcatg 1980

gataagtaca ggctgagctg cctggaggag gaacggctgc tgttggtggt gaccagtacg 2040

tttggcaatg gagactgccc tggcaatgga gagaaactga agaaatcgct cttcatgctg 2100

aaagagctca acaacaaatt caggtacgct gtgtttggcc tcggctccag catgtaccct 2160

cggttctgcg cctttgctca tgacattgat cagaagctgt cccacctggg ggcctctcag 2220

ctcaccccga tgggagaagg ggatgagctc agtgggcagg aggacgcctt ccgcagctgg 2280

gccgtgcaaa ccttcaaggc agcctgtgag acgtttgatg tccgaggcaa acagcacatt 2340

cagatcccca agctctacac ctccaatgtg acctgggacc cgcaccacta caggctcgtg 2400

caggactcac agcctttgga cctcagcaaa gccctcagca gcatgcatgc caagaacgtg 2460

ttcaccatga ggctcaaatc tcggcagaat ctacaaagtc cgacatccag ccgtgccacc 2520

atcctggtgg aactctcctg tgaggatggc caaggcctga actacctgcc gggggagcac 2580

cttggggttt gcccaggcaa ccagccggcc ctggtccaag gtatcctgga gcgagtggtg 2640

gatggcccca caccccacca gacagtgcgc ctggaggccc tggatgagag tggcagctac 2700

tgggtcagtg acaagaggct gcccccctgc tcactcagcc aggccctcac ctacttcctg 2760

gacatcacca cacccccaac ccagctgctg ctccaaaagc tggcccaggt ggccacagaa 2820

gagcctgaga gacagaggct ggaggccctg tgccagccct cagagtacag caagtggaag 2880

ttcaccaaca gccccacatt cctggaggtg ctagaggagt tcccgtccct gcgggtgtct 2940

gctggcttcc tgctttccca gctccccatt ctgaagccca ggttctactc catcagctcc 3000

tcccgggatc acacgcccac agagatccac ctgactgtgg ccgtggtcac ctaccacacc 3060

cgagatggcc agggtcccct gcaccacggc gtctgcagca catggctcaa cagcctgaag 3120

ccccaagacc cagtgccctg ctttgtgcgg aatgccagcg gcttccacct ccccgaggat 3180

ccctcccatc cttgcatcct catcgggcct ggcacaggca tcgcgccctt ccgcagtttc 3240

tggcagcaac ggctccatga ctcccagcac aagggagtgc ggggaggccg catgaccttg 3300

gtgtttgggt gccgccgccc agatgaggac cacatctacc aggaggagat gctggagatg 3360

gcccagaagg gggtgctgca tgcggtgcac acagcctatt cccgcctgcc tggcaagccc 3420

aaggtctatg ttcaggacat cctgcggcag cagctggcca gcgaggtgct ccgtgtgctc 3480

cacaaggagc caggccacct ctatgtttgc ggggatgtgc gcatggcccg ggacgtggcc 3540

cacaccctga agcagctggt ggctgccaag ctgaaattga atgaggagca ggtcgaggac 3600

tatttctttc agctcaagag ccagaagcgc tatcacgaag atatctttgg tgctgtattt 3660

ccttacgagg cgaagaagga cagggtggcg gtgcagccca gcagcctgga gatgtcagcg 3720

ctctgagggc ctacaggagg ggttaaagct gccggcacag aacttaagga tggagccagc 3780

tctgcattat ctgaggtcac agggcctggg gagatggagg aaagtgatat cccccagcct 3840

caagtcttat ttcctcaacg ttgctcccca tcaagccctt tacttgacct cctaacaagt 3900

agcaccctgg attgatcgga gcctcctctc tcaaactggg gcctccctgg tcccttggag 3960

acaaaatctt aaatgccagg cctggcaagt gggtgaaaga tggaacttgc tgctgagtgc 4020

accacttcaa gtgaccacca ggaggtgcta tcgcaccact gtgtatttaa ctgccttgtg 4080

tacagttatt tatgcctctg tatttaaaaa actaacaccc agtctgttcc ccatggccac 4140

ttgggtcttc cctgtatgat tccttgatgg agatatttac atgaattgca ttttacttta 4200

atcaca 4206

<210> 35

<211> 4507

<212> DNA

<213> Homo sapiens

<400> 35

gaccaattgt catacgactt gcagtgagcg tcaggagcac gtccaggaac tcctcagcag 60

cgcctccttc agctccacag ccagacgccc tcagacagca aagcctaccc ccgcgccgcg 120

ccctgcccgc cgctgcgatg ctcgcccgcg ccctgctgct gtgcgcggtc ctggcgctca 180

gccatacagc aaatccttgc tgttcccacc catgtcaaaa ccgaggtgta tgtatgagtg 240

tgggatttga ccagtataag tgcgattgta cccggacagg attctatgga gaaaactgct 300

caacaccgga atttttgaca agaataaaat tatttctgaa acccactcca aacacagtgc 360

actacatact tacccacttc aagggatttt ggaacgttgt gaataacatt cccttccttc 420

gaaatgcaat tatgagttat gtgttgacat ccagatcaca tttgattgac agtccaccaa 480

cttacaatgc tgactatggc tacaaaagct gggaagcctt ctctaacctc tcctattata 540

ctagagccct tcctcctgtg cctgatgatt gcccgactcc cttgggtgtc aaaggtaaaa 600

agcagcttcc tgattcaaat gagattgtgg aaaaattgct tctaagaaga aagttcatcc 660

ctgatcccca gggctcaaac atgatgtttg cattctttgc ccagcacttc acgcatcagt 720

ttttcaagac agatcataag cgagggccag ctttcaccaa cgggctgggc catggggtgg 780

acttaaatca tatttacggt gaaactctgg ctagacagcg taaactgcgc cttttcaagg 840

atggaaaaat gaaatatcag ataattgatg gagagatgta tcctcccaca gtcaaagata 900

ctcaggcaga gatgatctac cctcctcaag tccctgagca tctacggttt gctgtggggc 960

aggaggtctt tggtctggtg cctggtctga tgatgtatgc cacaatctgg ctgcgggaac 1020

acaacagagt atgcgatgtg cttaaacagg agcatcctga atggggtgat gagcagttgt 1080

tccagacaag caggctaata ctgataggag agactattaa gattgtgatt gaagattatg 1140

tgcaacactt gagtggctat cacttcaaac tgaaatttga cccagaacta cttttcaaca 1200

aacaattcca gtaccaaaat cgtattgctg ctgaatttaa caccctctat cactggcatc 1260

cccttctgcc tgacaccttt caaattcatg accagaaata caactatcaa cagtttatct 1320

acaacaactc tatattgctg gaacatggaa ttacccagtt tgttgaatca ttcaccaggc 1380

aaattgctgg cagggttgct ggtggtagga atgttccacc cgcagtacag aaagtatcac 1440

aggcttccat tgaccagagc aggcagatga aataccagtc ttttaatgag taccgcaaac 1500

gctttatgct gaagccctat gaatcatttg aagaacttac aggagaaaag gaaatgtctg 1560

cagagttgga agcactctat ggtgacatcg atgctgtgga gctgtatcct gcccttctgg 1620

tagaaaagcc tcggccagat gccatctttg gtgaaaccat ggtagaagtt ggagcaccat 1680

tctccttgaa aggacttatg ggtaatgtta tatgttctcc tgcctactgg aagccaagca 1740

cttttggtgg agaagtgggt tttcaaatca tcaacactgc ctcaattcag tctctcatct 1800

gcaataacgt gaagggctgt ccctttactt cattcagtgt tccagatcca gagctcatta 1860

aaacagtcac catcaatgca agttcttccc gctccggact agatgatatc aatcccacag 1920

tactactaaa agaacgttcg actgaactgt agaagtctaa tgatcatatt tatttattta 1980

tatgaaccat gtctattaat ttaattattt aataatattt atattaaact ccttatgtta 2040

cttaacatct tctgtaacag aagtcagtac tcctgttgcg gagaaaggag tcatacttgt 2100

gaagactttt atgtcactac tctaaagatt ttgctgttgc tgttaagttt ggaaaacagt 2160

ttttattctg ttttataaac cagagagaaa tgagttttga cgtcttttta cttgaatttc 2220

aacttatatt ataagaacga aagtaaagat gtttgaatac ttaaacactg tcacaagatg 2280

gcaaaatgct gaaagttttt acactgtcga tgtttccaat gcatcttcca tgatgcatta 2340

gaagtaacta atgtttgaaa ttttaaagta cttttggtta tttttctgtc atcaaacaaa 2400

aacaggtatc agtgcattat taaatgaata tttaaattag acattaccag taatttcatg 2460

tctacttttt aaaatcagca atgaaacaat aatttgaaat ttctaaattc atagggtaga 2520

atcacctgta aaagcttgtt tgatttctta aagttattaa acttgtacat ataccaaaaa 2580

gaagctgtct tggatttaaa tctgtaaaat cagtagaaat tttactacaa ttgcttgtta 2640

aaatatttta taagtgatgt tcctttttca ccaagagtat aaaccttttt agtgtgactg 2700

ttaaaacttc cttttaaatc aaaatgccaa atttattaag gtggtggagc cactgcagtg 2760

ttatcttaaa ataagaatat tttgttgaga tattccagaa tttgtttata tggctggtaa 2820

catgtaaaat ctatatcagc aaaagggtct acctttaaaa taagcaataa caaagaagaa 2880

aaccaaatta ttgttcaaat ttaggtttaa acttttgaag caaacttttt tttatccttg 2940

tgcactgcag gcctggtact cagattttgc tatgaggtta atgaagtacc aagctgtgct 3000

tgaataatga tatgttttct cagattttct gttgtacagt ttaatttagc agtccatatc 3060

acattgcaaa agtagcaatg acctcataaa atacctcttc aaaatgctta aattcatttc 3120

acacattaat tttatctcag tcttgaagcc aattcagtag gtgcattgga atcaagcctg 3180

gctacctgca tgctgttcct tttcttttct tcttttagcc attttgctaa gagacacagt 3240

cttctcatca cttcgtttct cctattttgt tttactagtt ttaagatcag agttcacttt 3300

ctttggactc tgcctatatt ttcttacctg aacttttgca agttttcagg taaacctcag 3360

ctcaggactg ctatttagct cctcttaaga agattaaaag agaaaaaaaa aggccctttt 3420

aaaaatagta tacacttatt ttaagtgaaa agcagagaat tttatttata gctaatttta 3480

gctatctgta accaagatgg atgcaaagag gctagtgcct cagagagaac tgtacggggt 3540

ttgtgactgg aaaaagttac gttcccattc taattaatgc cctttcttat ttaaaaacaa 3600

aaccaaatga tatctaagta gttctcagca ataataataa tgacgataat acttcttttc 3660

cacatctcat tgtcactgac atttaatggt actgtatatt acttaattta ttgaagatta 3720

ttatttatgt cttattagga cactatggtt ataaactgtg tttaagccta caatcattga 3780

tttttttttg ttatgtcaca atcagtatat tttctttggg gttacctctc tgaatattat 3840

gtaaacaatc caaagaaatg attgtattaa gatttgtgaa taaattttta gaaatctgat 3900

tggcatattg agatatttaa ggttgaatgt ttgtccttag gataggccta tgtgctagcc 3960

cacaaagaat attgtctcat tagcctgaat gtgccataag actgaccttt taaaatgttt 4020

tgagggatct gtggatgctt cgttaatttg ttcagccaca atttattgag aaaatattct 4080

gtgtcaagca ctgtgggttt taatattttt aaatcaaacg ctgattacag ataatagtat 4140

ttatataaat aattgaaaaa aattttcttt tgggaagagg gagaaaatga aataaatatc 4200

attaaagata actcaggaga atcttcttta caattttacg tttagaatgt ttaaggttaa 4260

gaaagaaata gtcaatatgc ttgtataaaa cactgttcac tgtttttttt aaaaaaaaaa 4320

cttgatttgt tattaacatt gatctgctga caaaacctgg gaatttgggt tgtgtatgcg 4380

aatgtttcag tgcctcagac aaatgtgtat ttaacttatg taaaagataa gtctggaaat 4440

aaatgtctgt ttatttttgt actatttaaa aattgacaga tcttttctga agaaaaaaaa 4500

aaaaaaa 4507

<210> 36

<211> 3875

<212> DNA

<213> Homo sapiens

<400> 36

agctgttctt ggctgacttc acatcaaaac tcctatactg acctgagaca gaggcagcag 60

tgatacccac ctgagagatc ctgtgtttga acaactgctt cccaaaacgg aaagtatttc 120

aagcctaaac ctttgggtga aaagaactct tgaagtcatg attgcttcac agtttctctc 180

agctctcact ttggtgcttc tcattaaaga gagtggagcc tggtcttaca acacctccac 240

ggaagctatg acttatgatg aggccagtgc ttattgtcag caaaggtaca cacacctggt 300

tgcaattcaa aacaaagaag agattgagta cctaaactcc atattgagct attcaccaag 360

ttattactgg attggaatca gaaaagtcaa caatgtgtgg gtctgggtag gaacccagaa 420

acctctgaca gaagaagcca agaactgggc tccaggtgaa cccaacaata ggcaaaaaga 480

tgaggactgc gtggagatct acatcaagag agaaaaagat gtgggcatgt ggaatgatga 540

gaggtgcagc aagaagaagc ttgccctatg ctacacagct gcctgtacca atacatcctg 600

cagtggccac ggtgaatgtg tagagaccat caataattac acttgcaagt gtgaccctgg 660

cttcagtgga ctcaagtgtg agcaaattgt gaactgtaca gccctggaat cccctgagca 720

tggaagcctg gtttgcagtc acccactggg aaacttcagc tacaattctt cctgctctat 780

cagctgtgat aggggttacc tgccaagcag catggagacc atgcagtgta tgtcctctgg 840

agaatggagt gctcctattc cagcctgcaa tgtggttgag tgtgatgctg tgacaaatcc 900

agccaatggg ttcgtggaat gtttccaaaa ccctggaagc ttcccatgga acacaacctg 960

tacatttgac tgtgaagaag gatttgaact aatgggagcc cagagccttc agtgtacctc 1020

atctgggaat tgggacaacg agaagccaac gtgtaaagct gtgacatgca gggccgtccg 1080

ccagcctcag aatggctctg tgaggtgcag ccattcccct gctggagagt tcaccttcaa 1140

atcatcctgc aacttcacct gtgaggaagg cttcatgttg cagggaccag cccaggttga 1200

atgcaccact caagggcagt ggacacagca aatcccagtt tgtgaagctt tccagtgcac 1260

agccttgtcc aaccccgagc gaggctacat gaattgtctt cctagtgctt ctggcagttt 1320

ccgttatggg tccagctgtg agttctcctg tgagcagggt tttgtgttga agggatccaa 1380

aaggctccaa tgtggcccca caggggagtg ggacaacgag aagcccacat gtgaagctgt 1440

gagatgcgat gctgtccacc agcccccgaa gggtttggtg aggtgtgctc attcccctat 1500

tggagaattc acctacaagt cctcttgtgc cttcagctgt gaggagggat ttgaattaca 1560

tggatcaact caacttgagt gcacatctca gggacaatgg acagaagagg ttccttcctg 1620

ccaagtggta aaatgttcaa gcctggcagt tccgggaaag atcaacatga gctgcagtgg 1680

ggagcccgtg tttggcactg tgtgcaagtt cgcctgtcct gaaggatgga cgctcaatgg 1740

ctctgcagct cggacatgtg gagccacagg acactggtct ggcctgctac ctacctgtga 1800

agctcccact gagtccaaca ttcccttggt agctggactt tctgctgctg gactctccct 1860

cctgacatta gcaccatttc tcctctggct tcggaaatgc ttacggaaag caaagaaatt 1920

tgttcctgcc agcagctgcc aaagccttga atcagatgga agctaccaaa agccttctta 1980

catcctttaa gttcaaaaga atcagaaaca ggtgcatctg gggaactaga gggatacact 2040

gaagttaaca gagacagata actctcctcg ggtctctggc ccttcttgcc tactatgcca 2100

gatgccttta tggctgaaac cgcaacaccc atcaccactt caatagatca aagtccagca 2160

ggcaaggacg gccttcaact gaaaagactc agtgttccct ttcctactct caggatcaag 2220

aaagtgttgg ctaatgaagg gaaaggatat tttcttccaa gcaaaggtga agagaccaag 2280

actctgaaat ctcagaattc cttttctaac tctcccttgc tcgctgtaaa atcttggcac 2340

agaaacacaa tattttgtgg ctttctttct tttgcccttc acagtgtttc gacagctgat 2400

tacacagttg ctgtcataag aatgaataat aattatccag agtttagagg aaaaaaatga 2460

ctaaaaatat tataacttaa aaaaatgaca gatgttgaat gcccacaggc aaatgcatgg 2520

agggttgtta atggtgcaaa tcctactgaa tgctctgtgc gagggttact atgcacaatt 2580

taatcacttt catccctatg ggattcagtg cttcttaaag agttcttaag gattgtgata 2640

tttttacttg cattgaatat attataatct tccatacttc ttcattcaat acaagtgtgg 2700

tagggactta aaaaacttgt aaatgctgtc aactatgata tggtaaaagt tacttattct 2760

agattacccc ctcattgttt attaacaaat tatgttacat ctgttttaaa tttatttcaa 2820

aaagggaaac tattgtcccc tagcaaggca tgatgttaac cagaataaag ttctgagtgt 2880

ttttactaca gttgtttttt gaaaacatgg tagaattgga gagtaaaaac tgaatggaag 2940

gtttgtatat tgtcagatat tttttcagaa atatgtggtt tccacgatga aaaacttcca 3000

tgaggccaaa cgttttgaac taataaaagc ataaatgcaa acacacaaag gtataatttt 3060

atgaatgtct ttgttggaaa agaatacaga aagatggatg tgctttgcat tcctacaaag 3120

atgtttgtca gatatgatat gtaaacataa ttcttgtata ttatggaaga ttttaaattc 3180

acaatagaaa ctcaccatgt aaaagagtca tctggtagat ttttaacgaa tgaagatgtc 3240

taatagttat tccctatttg ttttcttctg tatgttaggg tgctctggaa gagaggaatg 3300

cctgtgtgag caagcattta tgtttattta taagcagatt taacaattcc aaaggaatct 3360

ccagttttca gttgatcact ggcaatgaaa aattctcagt cagtaattgc caaagctgct 3420

ctagccttga ggagtgtgag aatcaaaact ctcctacact tccattaact tagcatgtgt 3480

tgaaaaaaaa gtttcagaga agttctggct gaacactggc aacaacaaag ccaacagtca 3540

aaacagagat gtgataagga tcagaacagc agaggttctt ttaaaggggc agaaaaactc 3600

tgggaaataa gagagaacaa ctactgtgat caggctatgt atggaataca gtgttatttt 3660

ctttgaaatt gtttaagtgt tgtaaatatt tatgtaaact gcattagaaa ttagctgtgt 3720

gaaataccag tgtggtttgt gtttgagttt tattgagaat tttaaattat aacttaaaat 3780

attttataat ttttaaagta tatatttatt taagcttatg tcagacctat ttgacataac 3840

actataaagg ttgacaataa atgtgcttat gttta 3875

<210> 37

<211> 1593

<212> DNA

<213> Homo sapiens

<400> 37

gcggtgccct tgcggcgcag ctggggtcgc ggccctgctc cccgcgcttt cttaaggccc 60

gcgggcggcg caggagcggc actcgtggct gtggtggctt cggcagcggc ttcagcagat 120

cggcggcatc agcggtagca ccagcactag cagcatgttg agccgggcag tgtgcggcac 180

cagcaggcag ctggctccgg ttttggggta tctgggctcc aggcagaagc acagcctccc 240

cgacctgccc tacgactacg gcgccctgga acctcacatc aacgcgcaga tcatgcagct 300

gcaccacagc aagcaccacg cggcctacgt gaacaacctg aacgtcaccg aggagaagta 360

ccaggaggcg ttggccaagg gagatgttac agcccagata gctcttcagc ctgcactgaa 420

gttcaatggt ggtggtcata tcaatcatag cattttctgg acaaacctca gccctaacgg 480

tggtggagaa cccaaagggg agttgctgga agccatcaaa cgtgactttg gttcctttga 540

caagtttaag gagaagctga cggctgcatc tgttggtgtc caaggctcag gttggggttg 600

gcttggtttc aataaggaac ggggacactt acaaattgct gcttgtccaa atcaggatcc 660

actgcaagga acaacaggcc ttattccact gctggggatt gatgtgtggg agcacgctta 720

ctaccttcag tataaaaatg tcaggcctga ttatctaaaa gctatttgga atgtaatcaa 780

ctgggagaat gtaactgaaa gatacatggc ttgcaaaaag taaaccacga tcgttatgct 840

gagtatgtta agctctttat gactgttttt gtagtggtat agagtactgc agaatacagt 900

aagctgctct attgtagcat ttcttgatgt tgcttagtca cttatttcat aaacaactta 960

atgttctgaa taatttctta ctaaacattt tgttattggg caagtgattg aaaatagtaa 1020

atgctttgtg tgattgaatc tgattggaca ttttcttcag agagctaaat tacaattgtc 1080

atttataaaa ccatcaaaaa tattccatcc atatactttg gggacttgta gggatgcctt 1140

tctagtccta ttctattgca gttatagaaa atctagtctt ttgccccagt tacttaaaaa 1200

taaaatatta acactttccc aagggaaaca ctcggctttc tatagaaaat tgcacttttt 1260

gtcgagtaat cctctgcagt gatacttctg gtagatgtca cccagtggtt tttgttaggt 1320

caaatgttcc tgtatagttt ttgcaaatag agctgtatac tgtttaaatg tagcaggtga 1380

actgaactgg ggtttgctca cctgcacagt aaaggcaaac ttcaacagca aaactgcaaa 1440

aaggtggttt ttgcagtagg agaaaggagg atgtttattt gcagggcgcc aagcaaggag 1500

aattgggcag ctcatgcttg agacccaatc tccatgatga cctacaagct agagtattta 1560

aaggcagtgg taaatttcag gaaagcagaa gtt 1593

<210> 38

<211> 4314

<212> DNA

<213> Homo sapiens

<400> 38

agacaggata ttcactgctg tggcaaggcc tgtagagagt ttcgaagtta ggaggactca 60

agacggtccc tccctggact tttctgaagg ggctcaaaag atgacacgcg ccagagctgg 120

aaggcgtcgc caattggtcc acttttccct cctccctttt tgcggatgag aaaactgagg 180

cccaggtttg ggatttccag agcccgggat ttcccggcaa cgcccgacaa ccacattccc 240

ccggctattc tgacccgccc cggttccggg acgctccctg ggagccgccg ccgagggcct 300

gctgggactc ccgggggacc ccgccgtcgg ggcagccccc acgcccggcg ccgcccgccg 360

ggaacggccg ccgctgttgc gcacttgcag gggagccggc gactgagggc gaggcaggga 420

gggagcaagc ggggctggga gggctgctgg cgcgggctcg cgcgctgtgt atggtctatc 480

gcaggcagct gacctttgag gaggaaatcg ctgctctccg ctccttcctg tagtaacagc 540

cgccgctgcc gccgccgcca ggaaccccgg ccgggagcga gagccgcggg gcgcagagcc 600

ggcccggctg ccggacggtg cggccccacc aggtgaacgg ccatggcggg ctggatccag 660

gcccagcagc tgcagggaga cgcgctgcgc cagatgcagg tgctgtacgg ccagcacttc 720

cccatcgagg tccggcacta cttggcccag tggattgaga gccagccatg ggatgccatt 780

gacttggaca atccccagga cagagcccaa gccacccagc tcctggaggg cctggtgcag 840

gagctgcaga agaaggcgga gcaccaggtg ggggaagatg ggtttttact gaagatcaag 900

ctggggcact acgccacgca gctccagaaa acatatgacc gctgccccct ggagctggtc 960

cgctgcatcc ggcacattct gtacaatgaa cagaggctgg tccgagaagc caacaattgc 1020

agctctccgg ctgggatcct ggttgacgcc atgtcccaga agcaccttca gatcaaccag 1080

acatttgagg agctgcgact ggtcacgcag gacacagaga atgagctgaa gaaactgcag 1140

cagactcagg agtacttcat catccagtac caggagagcc tgaggatcca agctcagttt 1200

gcccagctgg cccagctgag cccccaggag cgtctgagcc gggagacggc cctccagcag 1260

aagcaggtgt ctctggaggc ctggttgcag cgtgaggcac agacactgca gcagtaccgc 1320

gtggagctgg ccgagaagca ccagaagacc ctgcagctgc tgcggaagca gcagaccatc 1380

atcctggatg acgagctgat ccagtggaag cggcggcagc agctggccgg gaacggcggg 1440

ccccccgagg gcagcctgga cgtgctacag tcctggtgtg agaagttggc cgagatcatc 1500

tggcagaacc ggcagcagat ccgcagggct gagcacctct gccagcagct gcccatcccc 1560

ggcccagtgg aggagatgct ggccgaggtc aacgccacca tcacggacat tatctcagcc 1620

ctggtgacca gcacattcat cattgagaag cagcctcctc aggtcctgaa gacccagacc 1680

aagtttgcag ccaccgtacg cctgctggtg ggcgggaagc tgaacgtgca catgaatccc 1740

ccccaggtga aggccaccat catcagtgag cagcaggcca agtctctgct taaaaatgag 1800

aacacccgca acgagtgcag tggtgagatc ctgaacaact gctgcgtgat ggagtaccac 1860

caagccacgg gcaccctcag tgcccacttc aggaacatgt cactgaagag gatcaagcgt 1920

gctgaccggc ggggtgcaga gtccgtgaca gaggagaagt tcacagtcct gtttgagtct 1980

cagttcagtg ttggcagcaa tgagcttgtg ttccaggtga agactctgtc cctacctgtg 2040

gttgtcatcg tccacggcag ccaggaccac aatgccacgg ctactgtgct gtgggacaat 2100

gcctttgctg agccgggcag ggtgccattt gccgtgcctg acaaagtgct gtggccgcag 2160

ctgtgtgagg cgctcaacat gaaattcaag gccgaagtgc agagcaaccg gggcctgacc 2220

aaggagaacc tcgtgttcct ggcgcagaaa ctgttcaaca acagcagcag ccacctggag 2280

gactacagtg gcctgtccgt gtcctggtcc cagttcaaca gggagaactt gccgggctgg 2340

aactacacct tctggcagtg gtttgacggg gtgatggagg tgttgaagaa gcaccacaag 2400

ccccactgga atgatggggc catcctaggt tttgtgaata agcaacaggc ccacgacctg 2460

ctcatcaaca agcccgacgg gaccttcttg ttgcgcttta gtgactcaga aatcgggggc 2520

atcaccatcg cctggaagtt tgactccccg gaacgcaacc tgtggaacct gaaaccattc 2580

accacgcggg atttctccat caggtccctg gctgaccggc tgggggacct gagctatctc 2640

atctatgtgt ttcctgaccg ccccaaggat gaggtcttct ccaagtacta cactcctgtg 2700

ctggctaaag ctgttgatgg atatgtgaaa ccacagatca agcaagtggt ccctgagttt 2760

gtgaatgcat ctgcagatgc tgggggcagc agcgccacgt acatggacca ggccccctcc 2820

ccagctgtgt gcccccaggc tccctataac atgtacccac agaaccctga ccatgtactc 2880

gatcaggatg gagaattcga cctggatgag accatggatg tggccaggca cgtggaggaa 2940

ctcttacgcc gaccaatgga cagtcttgac tcccgcctct cgccccctgc cggtcttttc 3000

acctctgcca gaggctccct ctcatgaatg tttgaatccc acgcttctct ttggaaacaa 3060

tatgcaatgt gaagcggtcg tgttgtgagt ttagtaaggc tgtgtacact gacacctttg 3120

caggcatgca tgtgcttgtg tgtgtgtgtg tgtgtgtgtc cttgtgcatg agctacgcct 3180

gcctcccctg tgcagtcctg ggatgtggct gcagcagcgg tggcctcttt tcagatcatg 3240

gcatccaaga gtgcgccgag tctgtctctg tcatggtaga gaccgagcct ctgtcactgc 3300

aggcactcaa tgcagccaga cctattcctc ctgggcccct catctgctca gcagctattt 3360

gaatgagatg attcagaagg ggaggggaga caggtaacgt ctgtaagctg aagtttcact 3420

ccggagtgag aagctttgcc ctcctaagag agagagacag agagacagag agagagaaag 3480

agagagtgtg tgggtctatg taaatgcatc tgtcctcatg tgttgatgta accgattcat 3540

ctctcagaag ggaggctggg gttcattttc gagtagtatt ttatacttta gtgaacgtgg 3600

actccagact ctctgtgaac cctatgagag cgcgtctggg cccggccatg tccttagcac 3660

aggggggccg ccggtttgag tgagggtttc tgagctgctc tgaattagtc cttgcttggc 3720

tgcttggcct tgggcttcat tcaagtctat gatgctgttg cccacgtttc ccgggatata 3780

tattctctcc cctccgttgg gccccagcct tctttgcttg cctctctgtt tgtaaccttg 3840

tcgacaaaga ggtagaaaag attgggtcta ggatatggtg ggtggacagg ggccccggga 3900

cttggagggt tggtcctctt gcctcctgga aaaaacaaaa acaaaaaact gcagtgaaag 3960

acaagctgca aatcagccat gtgctgcgtg cctgtggaat ctggagtgag gggtaaaagc 4020

tgatctggtt tgactccgct ggaggtgggg cctggagcag gccttgcgct gttgcgtaac 4080

tggctgtgtt ctggtgaggc cttgctccca accccacacg ctcctccctc tgaggctgta 4140

ggactcgcag tcaggggcag ctgaccatgg aagattgaga gcccaaggtt taaacttctc 4200

tgaagggagg tggggatgag aagaggggtt tttttgtact ttgtacaaag accacacatt 4260

tgtgtaaaca gtgttttgga ataaaatatt tttttcataa aaaaaaaaaa aaaa 4314

<210> 39

<211> 1686

<212> DNA

<213> Homo sapiens

<400> 39

cagacgctcc ctcagcaagg acagcagagg accagctaag agggagagaa gcaactacag 60

accccccctg aaaacaaccc tcagacgcca catcccctga caagctgcca ggcaggttct 120

cttcctctca catactgacc cacggctcca ccctctctcc cctggaaagg acaccatgag 180

cactgaaagc atgatccggg acgtggagct ggccgaggag gcgctcccca agaagacagg 240

ggggccccag ggctccaggc ggtgcttgtt cctcagcctc ttctccttcc tgatcgtggc 300

aggcgccacc acgctcttct gcctgctgca ctttggagtg atcggccccc agagggaaga 360

gttccccagg gacctctctc taatcagccc tctggcccag gcagtcagat catcttctcg 420

aaccccgagt gacaagcctg tagcccatgt tgtagcaaac cctcaagctg aggggcagct 480

ccagtggctg aaccgccggg ccaatgccct cctggccaat ggcgtggagc tgagagataa 540

ccagctggtg gtgccatcag agggcctgta cctcatctac tcccaggtcc tcttcaaggg 600

ccaaggctgc ccctccaccc atgtgctcct cacccacacc atcagccgca tcgccgtctc 660

ctaccagacc aaggtcaacc tcctctctgc catcaagagc ccctgccaga gggagacccc 720

agagggggct gaggccaagc cctggtatga gcccatctat ctgggagggg tcttccagct 780

ggagaagggt gaccgactca gcgctgagat caatcggccc gactatctcg actttgccga 840

gtctgggcag gtctactttg ggatcattgc cctgtgagga ggacgaacat ccaaccttcc 900

caaacgcctc ccctgcccca atccctttat taccccctcc ttcagacacc ctcaacctct 960

tctggctcaa aaagagaatt gggggcttag ggtcggaacc caagcttaga actttaagca 1020

acaagaccac cacttcgaaa cctgggattc aggaatgtgt ggcctgcaca gtgaagtgct 1080

ggcaaccact aagaattcaa actggggcct ccagaactca ctggggccta cagctttgat 1140

ccctgacatc tggaatctgg agaccaggga gcctttggtt ctggccagaa tgctgcagga 1200

cttgagaaga cctcacctag aaattgacac aagtggacct taggccttcc tctctccaga 1260

tgtttccaga cttccttgag acacggagcc cagccctccc catggagcca gctccctcta 1320

tttatgtttg cacttgtgat tatttattat ttatttatta tttatttatt tacagatgaa 1380

tgtatttatt tgggagaccg gggtatcctg ggggacccaa tgtaggagct gccttggctc 1440

agacatgttt tccgtgaaaa cggagctgaa caataggctg ttcccatgta gccccctggc 1500

ctctgtgcct tcttttgatt atgtttttta aaatatttat ctgattaagt tgtctaaaca 1560

atgctgattt ggtgaccaac tgtcactcat tgctgagcct ctgctcccca ggggagttgt 1620

gtctgtaatc gccctactat tcagtggcga gaaataaagt ttgcttagaa aagaaaaaaa 1680

aaaaaa 1686

<210> 40

<211> 4180

<212> DNA

<213> Homo sapiens

<400> 40

ccagggtgat gctgaagatg atgaccttct tccaaggcct ctagagccat cagcctgtgc 60

caggcaccct cgacttgcct agaggccccc aaaagttgca gtccacatca gaggcagagt 120

cagaggcctc catgtcggag gcctcctctg aggacctggt gccacccctg gaggctgggg 180

cagccccata tagggaggag gaagaggcgg cgaagaagaa gaaggagaag aagaagaagt 240

ccaaaggcct ggccaatgtg ttctgcgtct tcaccaaagg gaagaagaag aagggtcagc 300

ccagctcagc ggagcccgag gacgcagccg ggtccaggca ggggctggat ggcccgcccc 360

ccacagtgga ggagctgaag gcggcgctgg agcgcgggca gctggaggcg gcgcggccgc 420

tgctggcgct ggagcgggag ctggcggcgg cggcggcggc gggcggtgtg agcgaggagg 480

agctggtgcg gcgccagagc aaggtggagg cgctgtacga gctgctgcgc gaccaggtgc 540

tgggcgtgct gcggcggccg ctggaggcgc cgcccgagcg gctgcgccag gcgctggccg 600

tggtggcgga gcaggagcgc gaggaccgcc aggcggcggc ggcggggccg gggacctcgg 660

ggctggcggc cacgcgcccg cggcgctggc tgcagctgtg gcggcgcggc gtggcggagg 720

cggccgagga gcgcatgggc cagcggccgg ccgcgggcgc cgaggtcccc gagagcgtct 780

ttctgcactt gggccgcacc atgaaggagg acctggaggc cgtggtggag cggctgaagc 840

cgctgttccc cgccgagttc ggcgtcgtgg cggcctacgc cgagagctac caccagcact 900

tcgcggccca cctggccgcc gtggcgcagt tcgagctgtg cgagcgcgac acctacatgc 960

tgctgctctg ggtgcagaac ctctacccca atgacatcat caacagcccc aagctggtgg 1020

gtgagctgca gggtatgggg ctcgggagcc tcctgccccc caggcagatc cgactgctgg 1080

aggccacatt cctgtccagt gaggcggcca atgtgaggga gttgatggac cgagctctgg 1140

agctagaggc acggcgctgg gctgaggatg tgcctcccca gaggctggac ggccactgcc 1200

acagcgagct ggccatcgac atcatccaga tcacctccca ggcccaggcc aaggccgaga 1260

gcatcacgct ggacttgggc tcacagataa agcgggtgct gctggtggag ctgcctgcgt 1320

tcctgaggag ctaccagcgc gcctttaatg aatttctgga gagaggcaag cagctgacga 1380

attacagggc caatgttatt gccaacatca acaactgcct gtccttccgg atgtccatgg 1440

agcagaattg gcaggtaccc caggacaccc tgagcctcct gctgggcccc ctgggtgagc 1500

tcaagagcca cggctttgac accctgctcc agaacctgca tgaggacctg aagccactgt 1560

tcaagaggtt cacgcacacc cgctgggcgg cccctgtgga gaccctggaa aacatcatcg 1620

ccactgtaga cacgaggctg cctgagttct cagagctgca gggctgtttc cgggaggagc 1680

tcatggaggc cttgcacctg cacctggtga aggagtacat catccaactc agcaaggggc 1740

gcctggtcct caagacggcc gagcagcagc agcagctggc tgggtacatc ctggccaatg 1800

ctgacaccat ccagcacttc tgcacccagc acggctcccc ggcgacctgg ctgcagcctg 1860

ctctccctac gctggccgag atcattcgcc tgcaggaccc cagtgccatc aagattgagg 1920

tggccactta tgccacctgc taccctgact tcagcaaagg ccacctgagc gctatcctgg 1980

ccatcaaggg gaacctatcc aacagtgagg tcaagcgcat ccggagcatc ttggacgtca 2040

gcatgggggc gcaggagccc tcccggcccc tattttccct tataaaggtt ggttagcttt 2100

tcctgtggcc tgacctgcct gtgagtgccc agcaagcctt gggcacaccc cgctgggagc 2160

tgttaagagc agcgctggtt ctcggttcct cccgggtctc ctgtgctctg atgctacttc 2220

tgcctagccc tggcggaggt gcaggccctg tcagctggaa ctggacagac cttggtttgt 2280

ttacatgtcc gatgggggca ggagctccca tcctgggcag ccaaccaggc aacaccaagg 2340

actctttgta aacgatagct gatcgtgtgc acgcaaggaa agaaccagga gggagagtgc 2400

agccaggctc agggatcccc ggacacctct gtccagagcc cctccacagt cggcctcatg 2460

actgtcctcc tcgtgggtgg ggccgagggc cctcttcagc tctctggaga caggggccga 2520

gcctcaccca tctgccctct gcagcccagg gccgccgtga gcgggattca gcaatggtgg 2580

aatggaagac agaactggaa gagaaagaag gaaaagatga gctctcgtct ggcaggggct 2640

tttagggtcc tgtggcgagc tgtgagcacc gccagcatta gacgtcacat ccaggtggcc 2700

ccacggcccc tacaggctgg ccctgcaatg gggccctgag ccctccctct tcatccccca 2760

aggcctcaac tagagggtgg tcccccgagg gcttggtgtc tactaccgaa gggcccaaga 2820

cctcctgggt cctctcaggc tcccccttcc ccaaggcagg gacaggccct gggggtgcca 2880

ccgtgggccc tgccacccag aagtctggct gaggtctggg caggggcagg gcaagcttga 2940

cctctcactg ttgacccttt ggcctctgta tttgtttcct attgccgtga caggtttcca 3000

caaacttcgt ggatcaaaac gaggtcttcc agttctgcgg gtcagaaggc tgacccgggg 3060

ctcaaatctg ggtgtcggca gtcctgcact ccttctggag gctctagggg agaattcatt 3120

tctggccttt tcatttttag aggctgaccg taattcttga cttcaggctc ctccatcttc 3180

agagccagct gtgggtagtt gaatcttttt cccgtcacct cattgaggcc tcccctctcc 3240

tgcctccctc caccactttt tttttttttt ttttgagaca gggtcttgct gtgttgccca 3300

ggctggagtg cagtggcctg gtcatggcat caaggctcac tgcagcctgg acctcctggt 3360

tcaagtgatc ctcttgtctc agtcccctga gacaatcccc cacgcccagc tacatatttt 3420

ttgtggatac agggtctcat tctgttgcct aggcttgtct ggaactcctg ggctcaaggg 3480

atcttgtagc cttagcctcc taaagtgctg ggattatagg catgagtcac tgtacccggc 3540

ctgctctacc gcttttaagg acgcttatga tcacattgcg cctacccaga gaacccaggt 3600

cgtctttcta ttttcaggtc agctgattag ccaccttagt tccatctgca actttagttc 3660

ccactggctg tgtaacctaa catagtcaca ggctctgggg actgtcacgt ggacatcttt 3720

gggaggccgt tattctgccc accgcaccct ccgttcatcc cctgccctgc cgggcacctc 3780

gctctacccc aggaaaatgt gagctcgttt tcctgctcgg catgtgctcc ccctaaggct 3840

ctgctcctcc ctgggcctga aagttccttc tcagcctgag agggggccct tcggactcag 3900

gcatgactca gcccggctga tgcctctgca gtgctgagtc aggatttggg gccggctctc 3960

ttgggtccgt ccccttttcc caggtactgc cttacaaagc tgtggccagg aagtggccgg 4020

tataaaggat gcccaaggtc tttgtacgtg tgtaggagtt agcgtgtttg atattgttaa 4080

tataataata attatttttt agagtactgc ttttgtatgt atgttgaaca ggatccaggt 4140

ttttatagct tgatataaaa cagaattcaa aagtgaaaaa 4180

<210> 41

<211> 2933

<212> DNA

<213> Homo sapiens

<400> 41

agtctccggg gactttccca ggggtggggc ggcccggcca ggcccccggc acttcctcgt 60

cctcggcccg ggtgccctgc ccccgtccag gagccctagg agtgctacgg ggggccggag 120

ccttgcccgg gccgctgccc cgtccctgga ttcggggctg gacgcagcaa gcggggcgct 180

gtgtccccaa gctccccgtc ctcggccagg cgggcaccac ggcaggggct gagctaccct 240

catggaaggg agaggaccgt accggatcta cgaccctggg ggcagcgtgc cctcaggaga 300

ggcatccgca gcttttgagc gcctagtgaa ggagaattcc cggctgaagg aaaaaatgca 360

agggataaag atgttagggg agcttttgga agagtcccag atggaagcga ccaggctccg 420

gcagaaggca gaggagctag tgaaggacaa cgagctgctc ccaccacctt ctccctcctt 480

gggctccttc gaccccctgg ctgagctcac aggaaaggac tcaaatgtca cagcatctcc 540

cacagcccct gcatgcccca gtgacaagcc agcaccagtc cagaagcctc catccagtgg 600

cacctcctct gaatttgaag tggtcactcc tgaggagcag aattcaccag agagcagcag 660

ccatgccaat gcgatggcgc tgggccccct gccccgtgag gacggcaacc tgatgctgca 720

cctgcagcgc ctggagacca cgctgagtgt gtgtgccgag gagccggacc acggccagct 780

cttcacccac ctgggccgca tggccctgga gttcaaccga ctggcatcca aggtgcacaa 840

gaatgagcag cgcacctcca ttctgcagac cctgtgtgag cagcttcgga aggagaacga 900

ggctctgaag gccaagttgg ataagggcct ggaacagcgg gatcaggctg ccgagaggct 960

gcgggaggaa aatttggagc tcaagaagtt gttgatgagc aatggcaaca aagagggtgc 1020

gtctgggcgg ccaggctcac cgaagatgga agggacaggc aagaaggcag tggctggaca 1080

gcagcaggct agtgtgacgg caggtaaggt cccagaggtg gtggccttgg gcgcagccga 1140

gaagaaggtg aagatgctgg agcagcagcg cagtgagctg ctggaagtga acaagcagtg 1200

ggaccagcat ttccggtcca tgaagcagca gtatgagcag aagatcactg agctgcgtca 1260

gaagctggct gatttgcaga agcaggtgac tgacctggag gccgagcggg agcagaagca 1320

gcgtgacttt gaccgcaagc tcctcctggc caagtccaag attgaaatgg aggagaccga 1380

caaggagcag ctgacagcag aggccaagga gctgcgccaa aaggtcaagt acctgcagga 1440

tcagctgagc ccactcaccc gacagcgtga gtaccaggaa aaggagatcc agcggctcaa 1500

caaggccctg gaggaagcac tgagcatcca aaccccgcca tcatctccac caacagcatt 1560

tgggagccca gaaggagcag gggccctcct aaggaaacag gagctggtca cgcagaatga 1620

gttgctgaaa cagcaggtga agatcttcga ggaggacttc cagagggagc gcagtgatcg 1680

tgagcgcatg aatgaggaga aggaagagct gaagaagcaa gtggagaagc tgcaggccca 1740

ggtcaccctg tcaaatgccc agctaaaagc attcaaagat gaggagaagg caagagaagc 1800

cctcagacag cagaagagga aagcaaaggc ctcaggagag cgttaccatg tggagcccca 1860

cccagaacat ctctgcgggg cctaccccta cgcctacccg cccatgccag ccatggtgcc 1920

acaccatggc ttcgaggact ggtcccagat ccgctacccc cctcccccca tggccatgga 1980

gcacccgccc ccactcccca actcgcgcct cttccatctg ccggaataca cctggcgtct 2040

accctgtgga ggggttcgaa atccaaatca gagctcccaa gtgatggacc ctcccacagc 2100

caggcctaca gaaccagagt ctccaaaaaa tgaccgtgag gggcctcagt gagaccagat 2160

tgtgtcattt ggctccacct tcatcttgca gagccagctg atctcagatt gccaagaaac 2220

tagaagccac ttgcacggtg tggccagagc ctcagctgga tgagaggctg agatgggtgg 2280

ccagcttgta caccagtccc tgaactgagc tgtttacagg actggggagg ctccacccag 2340

aaggctttca tttgtactct gctgggagtg actgggaaaa actccttccc tgctgctgag 2400

tggagagagg cctcatccgg ctttgaccca ccatccgttg cagaagcctc caggagcagc 2460

aatcctaaga gtgggaggca gccaagaccc ccttccttca aaacctcccg gaagtggttt 2520

caggccctct agttgccatg accaatttgt gtgtgtgttt aatttttgct tcaagctctg 2580

tagcaggacc tgccccacgc acacccctac ccctctgtga ggagctgtgg gaagtgtggg 2640

tttgtctcca gaacagaaga gaatgatgga tattctggct ctggggccct ctccaccacc 2700

actcacagta gccttgctga agccatcaca gatgggagaa ggccatgcca gccacgtccg 2760

ccgaggggcg ccagcctgaa gctgccaggc cctgaggttc agaccctgga ccccatagct 2820

ggaggcctgt ggtgccagaa gcccagatta gggtggctgt ccatccctgg atagctattt 2880

gcacgaatca tggacataaa tccaagttga agaagatcaa caaaaaaaaa aaa 2933

<210> 42

<211> 4450

<212> DNA

<213> Homo sapiens

<400> 42

gtaaagtggt ggcacctgac cggagcatgt agccacctat gacttcctga gtggggtggt 60

gtggggaggg ccctgaggag tctgtggtcc taggccttgg atttcatcag ggctttcctg 120

ctccttctgg ttgcctcagt cccaggcaag atagggtccc agaatcttac agcccagagg 180

ccacctgttg caacttcttt tttacagatg gagtcatcag aacccactgt gaggaagtga 240

cttctccttg aggtcaccca gacactccaa acagagcaga gcaaaagcgc ctagaacttg 300

aaattttgga cctgtctcca acaccctggg gatttccacc aggaagcctt cagtcaccat 360

ccaggggatt tttatcgcca caaagggtaa ttcctgctcc atccctgctg tgactcagct 420

gtgacgttga accacacaag ccagagagaa gaagataaag tcatcagagc tcctactcac 480

cagagagtga ggcccaggcc aggactccac aaggctggtc ccctgccctg gagcaactta 540

aacaggccct ctggccagcc tggaaccctg agatggcctc cagctcaggc agcagtcctc 600

gcccggcccc tgatgagaat gagtttccct ttgggtgccc tcccaccgtc tgccaggacc 660

caaaggagcc cagggctctc tgctgtgcag gctgtctctc tgagaacccg aggaatggcg 720

aggatcagat ctgccccaaa tgcagagggg aagacctcca gtctataagc ccaggaagcc 780

gtcttcgaac tcaggagaag gctcaccccg aggtggctga ggctggaatt gggtgcccct 840

ttgcaggtgt cggctgctcc ttcaagggaa gcccacagtc tgtgcaagag catgaggtca 900

cctcccagac ctcccaccta aacctgctgt tggggttcat gaaacagtgg aaggcccggc 960

tgggctgtgg cctggagtct gggcccatgg ccctggagca gaacctgtca gacctgcagc 1020

tgcaggcagc cgtggaagtg gcgggggacc tggaggtcga ttgctaccgg gcaccctgct 1080

ccgagagcca ggaggagctg gccctgcagc acttcatgaa ggagaagctt ctggctgagc 1140

tggaggggaa gctgcgtgtg tttgagaaca ttgttgctgt cctcaacaag gaggtggagg 1200

cctcccacct ggccctggcc acctctatcc accagagcca gctggaccgt gagcgcatcc 1260

tgagcttgga gcagagggtg gtggagcttc agcagaccct ggcccagaaa gaccaggccc 1320

tgggcaagct ggagcagagc ttgcgcctca tggaggaggc ctccttcgat ggcactttcc 1380

tgtggaagat caccaatgtc accaggcggt gccatgagtc ggcctgtggc aggaccgtca 1440

gcctcttctc cccagccttc tacactgcca agtatggcta caagttgtgc ctgcggctgt 1500

acctgaatgg agatggcact ggaaagagaa cccatctgtc gctcttcatc gtgatcatga 1560

gaggggagta tgatgcgctg ctgccgtggc ccttccggaa caaggtcacc ttcatgctgc 1620

tggaccagaa caaccgtgag cacgccattg acgccttccg gcctgaccta agctcagcgt 1680

ccttccagag gccccagagt gaaaccaacg tggccagtgg atgcccactc ttcttccccc 1740

tcagcaaact gcagtcaccc aagcacgcct acgtgaagga cgacacaatg ttcctcaagt 1800

gcattgtgga gaccagcact tagggtgggc ggggctcctg agggagctcc aactcagaag 1860

ggagctagcc agaggactgt gatgccctgc ccttggcacc caagacctca gggcacaaag 1920

atgggtgaag gctggcatga tccaagcaag actgaggggt cgacttcggg ctggccatct 1980

ggttaggatg gcaggacgtg ggctgggccc acaaaggcaa agggtccaga aggagacagg 2040

cagagctgct cccctctgca cggaccatgc gacactggga ggccagtgag ccactccggc 2100

cccgaatgtt gaggtggact ctcaccaaat gagaagaaaa tggaaccagg cttggaaccg 2160

taggacccaa gcagagaagc tctcgggcta ggaagatctc tgcagggccg ccagggagac 2220

ctggacacag gcctgctctc tttttctcca gggtcagaaa caggaccggg tggaagggat 2280

ggggtgccag tttgaatgca gtctgtccag gctcgtcatt ggaggtgaac aagcaaaccc 2340

agacggctcc actaggactt caaattgggg gttggatttg aagactttta agtttccttc 2400

cagcccagaa agtctctcat tctaggcctc ctggcccagg tgagtcctag agctacaggg 2460

gttctggaaa cattcaggag cttcctgtcc tcccagctcc tcactcacct tcagtaaccc 2520

ccactggact gacctggtcc acagggcacc tgccaccctg ggcctggcag ctcagcttcc 2580

ccaacacgca ggagcacacc cagcccccac atcctgtgcc tccatcagct aaacaccacg 2640

tcacttcatg caggtgaaac ccagtcactg tgagctccca ggtgcagcca gaggcacctc 2700

aagaagaaga ggggcataaa ctttcctctt cctgcctaga ggccccacct ttggtgcttt 2760

ccagaatccc gtaacacctg attaactgag gcatccactt ctttcagcag actgatcagg 2820

acctccaagc cactgagcaa tgtataaccc caaagaaata atttttagaa tctctttcga 2880

agttttccta aagtgtatgg tttgggagtt gtttgtactg agccaggttt gaaaaggcca 2940

ttgctgagtt tgaggtggtg ccaccagttt tgcaggtggc atcagaggct ggcatgctgg 3000

caggaacatc ccctcttagc cccagtcttc tcttttctat aatgagaccc accccagctt 3060

gcctccctcc ctggcttctc tgaccctcaa aggagatgcc acgcaggaca gactggagag 3120

agaagcctgg gcaatactgc ccgcctgtca tggcctggtg gtggcccaca cctatcttct 3180

caccttggag gccacaccca actttccaaa gaccctgaga caagtcagga ccctactact 3240

ctcccctgct gctttcctga cagcttactc ttcctccacc tgctgagcct gtgccagact 3300

ccattgctca aatcgttagg gttgcttcta taaaaatggg tcagtagccc ttcctgttct 3360

ctccagccca gcatacagga ggatcaaagg aggtgacgga gcatcgtggc acggcagtct 3420

caatgggtca gaaacccagg ccagctgggc tctaagcctg gcatcctgtc atgcttagtc 3480

cttcagctga agatcagagg aagcctctcc cttgccctct ccagctctag gggttttcag 3540

gaggcccaac tgcaataatg gagcactagt gcttttatgt gcaatggtgt cgtccatgca 3600

cgacagcagc aaacattctg gggctgcttt ttattgttcc cacggctgac agcgtggcag 3660

cggagactgt ggaggcagtg gagactgact tcttcctgct gacagctgga tgtcacacat 3720

gaaggtctgg cctagcgagt gatgggtcta ggccctgaaa ctgatgtcct agcaataacc 3780

tcttgatccc tactcaccga gtgttgagcc caagggggga tttgtagaac aagcccccat 3840

gagaaacagc tgttactcta cacttttgat tgcctatttc tgatggcaag agatacatac 3900

tctcttcaaa gagcatgaga tgcagccatt ctttcagcaa agcttcattg acacctgcac 3960

ctgttaactg tgttcgacat tgaagggaga aaggcaagat gtgcactctg gactcaagaa 4020

actcttagtt cagtggagga aatgagcaga taagtagatc attatgattg agagtaggag 4080

aagcttagag aaagcacaga atcccagatc cagctggtga aggagggaag gcttcaggcc 4140

tttaagctca gcctgagaat attgtgaaat gcagaggatg gggaaaaggg aagagtaccg 4200

acttgaaaac ggagagctgt cttggctgag ggcagggtct gtgtggcagg atgggggagg 4260

gagtcagaag ggtcagatga actggagtgt agacagcatc agatgcagca gtgcccaccg 4320

cccccccccc caccccccgc cctgcccaca gagcacctgc tggtaaccct gggcctattg 4380

aaagcaggat gagatgataa tttaagacac tgaatgattt cttttccaac aaagctctat 4440

gttaagtgca 4450

<210> 43

<211> 3220

<212> DNA

<213> Homo sapiens

<400> 43

aaactttttt ccctggctct gccctgggtt tccccttgaa gggatttccc tccgcctctg 60

caacaagacc ctttataaag cacagacttt ctatttcact ccgcggtatc tgcatcgggc 120

ctcactggct tcaggagctg aataccctcc caggcacaca caggtgggac acaaataagg 180

gttttggaac cactattttc tcatcacgac agcaacttaa aatgcctggg aagatggtcg 240

tgatccttgg agcctcaaat atactttgga taatgtttgc agcttctcaa gcttttaaaa 300

tcgagaccac cccagaatct agatatcttg ctcagattgg tgactccgtc tcattgactt 360

gcagcaccac aggctgtgag tccccatttt tctcttggag aacccagata gatagtccac 420

tgaatgggaa ggtgacgaat gaggggacca catctacgct gacaatgaat cctgttagtt 480

ttgggaacga acactcttac ctgtgcacag caacttgtga atctaggaaa ttggaaaaag 540

gaatccaggt ggagatctac tcttttccta aggatccaga gattcatttg agtggccctc 600

tggaggctgg gaagccgatc acagtcaagt gttcagttgc tgatgtatac ccatttgaca 660

ggctggagat agacttactg aaaggagatc atctcatgaa gagtcaggaa tttctggagg 720

atgcagacag gaagtccctg gaaaccaaga gtttggaagt aacctttact cctgtcattg 780

aggatattgg aaaagttctt gtttgccgag ctaaattaca cattgatgaa atggattctg 840

tgcccacagt aaggcaggct gtaaaagaat tgcaagtcta catatcaccc aagaatacag 900

ttatttctgt gaatccatcc acaaagctgc aagaaggtgg ctctgtgacc atgacctgtt 960

ccagcgaggg tctaccagct ccagagattt tctggagtaa gaaattagat aatgggaatc 1020

tacagcacct ttctggaaat gcaactctca ccttaattgc tatgaggatg gaagattctg 1080

gaatttatgt gtgtgaagga gttaatttga ttgggaaaaa cagaaaagag gtggaattaa 1140

ttgttcaaga gaaaccattt actgttgaga tctcccctgg accccggatt gctgctcaga 1200

ttggagactc agtcatgttg acatgtagtg tcatgggctg tgaatcccca tctttctcct 1260

ggagaaccca gatagacagc cctctgagcg ggaaggtgag gagtgagggg accaattcca 1320

cgctgaccct gagccctgtg agttttgaga acgaacactc ttatctgtgc acagtgactt 1380

gtggacataa gaaactggaa aagggaatcc aggtggagct ctactcattc cctagagatc 1440

cagaaatcga gatgagtggt ggcctcgtga atgggagctc tgtcactgta agctgcaagg 1500

ttcctagcgt gtaccccctt gaccggctgg agattgaatt acttaagggg gagactattc 1560

tggagaatat agagtttttg gaggatacgg atatgaaatc tctagagaac aaaagtttgg 1620

aaatgacctt catccctacc attgaagata ctggaaaagc tcttgtttgt caggctaagt 1680

tacatattga tgacatggaa ttcgaaccca aacaaaggca gagtacgcaa acactttatg 1740

tcaatgttgc ccccagagat acaaccgtct tggtcagccc ttcctccatc ctggaggaag 1800

gcagttctgt gaatatgaca tgcttgagcc agggctttcc tgctccgaaa atcctgtgga 1860

gcaggcagct ccctaacggg gagctacagc ctctttctga gaatgcaact ctcaccttaa 1920

tttctacaaa aatggaagat tctggggttt atttatgtga aggaattaac caggctggaa 1980

gaagcagaaa ggaagtggaa ttaattatcc aagttactcc aaaagacata aaacttacag 2040

cttttccttc tgagagtgtc aaagaaggag acactgtcat catctcttgt acatgtggaa 2100

atgttccaga aacatggata atcctgaaga aaaaagcgga gacaggagac acagtactaa 2160

aatctataga tggcgcctat accatccgaa aggcccagtt gaaggatgcg ggagtatatg 2220

aatgtgaatc taaaaacaaa gttggctcac aattaagaag tttaacactt gatgttcaag 2280

gaagagaaaa caacaaagac tatttttctc ctgagcttct cgtgctctat tttgcatcct 2340

ccttaataat acctgccatt ggaatgataa tttactttgc aagaaaagcc aacatgaagg 2400

ggtcatatag tcttgtagaa gcacagaagt caaaagtgta gctaatgctt gatatgttca 2460

actggagaca ctatttatct gtgcaaatcc ttgatactgc tcatcattcc ttgagaaaaa 2520

caatgagctg agaggcagac ttccctgaat gtattgaact tggaaagaaa tgcccatcta 2580

tgtcccttgc tgtgagcaag aagtcaaagt aaaacttgct gcctgaagaa cagtaactgc 2640

catcaagatg agagaactgg aggagttcct tgatctgtat atacaataac ataatttgta 2700

catatgtaaa ataaaattat gccatagcaa gattgcttaa aatagcaaca ctctatattt 2760

agattgttaa aataactagt gttgcttgga ctattataat ttaatgcatg ttaggaaaat 2820

ttcacattaa tatttgctga cagctgacct ttgtcatctt tcttctattt tattcccttt 2880

cacaaaattt tattcctata tagtttattg acaataattt caggttttgt aaagatgccg 2940

ggttttatat ttttatagac aaataataag caaagggagc actgggttga ctttcaggta 3000

ctaaatacct caacctatgg tataatggtt gactgggttt ctctgtatag tactggcatg 3060

gtacggagat gtttcacgaa gtttgttcat cagactcctg tgcaactttc ccaatgtggc 3120

ctaaaaatgc aacttctttt tattttcttt tgtaaatgtt taggtttttt tgtatagtaa 3180

agtgataatt tctggaatta gaaaaaaaaa aaaaaaaaaa 3220

<210> 44

<211> 20

<212> DNA

<213> Homo sapiens

<400> 44

ggcagccttc ctgatttctg 20

<210> 45

<211> 21

<212> DNA

<213> Homo sapiens

<400> 45

ggtggaaagg tttggagtat g 21

<210> 46

<211> 24

<212> DNA

<213> Homo sapiens

<400> 46

cagctctgtg tgaaggtgca gttt 24

<210> 47

<211> 22

<212> DNA

<213> Homo sapiens

<400> 47

ggagttcatc cgtcaagttc aa 22

<210> 48

<211> 19

<212> DNA

<213> Homo sapiens

<400> 48

tttcatctcc tgggctgtc 19

<210> 49

<211> 24

<212> DNA

<213> Homo sapiens

<400> 49

accctcatct acttgaacag ctgct 25

<210> 50

<211> 20

<212> DNA

<213> Homo sapiens

<400> 50

tgcagtaata ctggggaacc 26

<210> 51

<211> 21

<212> DNA

<213> Homo sapiens

<400> 51

gcttcgtcag aatcacgttg g 21

<210> 52

<211> xx

<212> DNA

<213> Homo sapiens

<400> 52

tgaccatcta cagctttccg gcg 23

<210> 53

<211> 19

<212> DNA

<213> Homo sapiens

<400> 53

cctccactcc atcctgaag 19

<210> 54

<211> 20

<212> DNA

<213> Homo sapiens

<400> 54

gccatggata gaggctaagt 20

<210> 55

<211> 23

<212> DNA

<213> Homo sapiens

<400> 55

accaactaca atggccacac gtg 23

<210> 56

<211> 23

<212> DNA

<213> Homo sapiens

<400> 56

tttcaagaca gatcataagc gag 23

<210> 57

<211> 22

<212> DNA

<213> Homo sapiens

<400> 57

agccagagtt tcaccgtaaa ta 22

<210> 58

<211> 23

<212> DNA

<213> Homo sapiens

<400> 58

tgggccatgg ggtggactta aat 23

<210> 59

<211> 18

<212> DNA

<213> Homo sapiens

<400> 59

ccaaccgcga gaagatga 18

<210> 60

<211> 20

<212> DNA

<213> Homo sapiens

<400> 60

ccagaggcgt acagggatag 20

<210> 61

<211> 23

<212> DNA

<213> Homo sapiens

<400> 61

ccatgtacgt tgctatccag gct 23

<210> 62

<211> 19

<212> DNA

<213> Homo sapiens

<400> 62

agtcctgagt ccggatgaa 19

<210> 63

<211> 18

<212> DNA

<213> Homo sapiens

<400> 63

cctccctcag tcgtctct 18

<210> 64

<211> 24

<212> DNA

<213> Homo sapiens

<400> 64

tgacggaggg tggcatcaaa tacc 24

<210> 65

<211> 22

<212> DNA

<213> Homo sapiens

<400> 65

gccagcttgt cttcaatgaa at 22

<210> 66

<211> 21

<212> DNA

<213> Homo sapiens

<400> 66

caaagccagc ttctgttcaa g 21

<210> 67

<211> 24

<212> DNA

<213> Homo sapiens

<400> 67

atccaccatg agttggtagg cagc 24

<210> 68

<211> 23

<212> DNA

<213> Homo sapiens

<400> 68

gccaagaaga aagtgaacat cat 23

<210> 69

<211> 20

<212> DNA

<213> Homo sapiens

<400> 69

atagggattc cgggagtcat 20

<210> 70

<211> 24

<212> DNA

<213> Homo sapiens

<400> 70

tcagaacaac agcctgccac ctta 24

<210> 71

<211> 22

<212> DNA

<213> Homo sapiens

<400> 71

tgactccttc aacaccttct tc 22

<210> 72

<211> 18

<212> DNA

<213> Homo sapiens

<400> 72

tgccagtgcg aacttcat 18

<210> 73

<211> 24

<212> DNA

<213> Homo sapiens

<400> 73

ccgggctgtg tttgtagact tgga 24

<210> 74

<211> 17

<212> DNA

<213> Homo sapiens

<400> 74

agccacatca tccctgt 17

<210> 75

<211> 22

<212> DNA

<213> Homo sapiens

<400> 75

cgtagatgtt atgtctgctc at 22

<210> 76

<211> 22

<212> DNA

<213> Homo sapiens

<400> 76

tttagcagca tctgcaaccc gc 22

<210> 77

<211> 24

<212> DNA

<213> Homo sapiens

<400> 77

gaggatttgg aaagggtgtt tatt 24

<210> 78

<211> 21

<212> DNA

<213> Homo sapiens

<400> 78

acagagggct acaatgtgat g 21

<210> 79

<211> 26

<212> DNA

<213> Homo sapiens

<400> 79

acgtcttgct cgagatgtga tgaagg 26

<210> 80

<211> 18

<212> DNA

<213> Homo sapiens

<400> 80

taaaccctgc gtggcaat 18

<210> 81

<211> 27

<212> DNA

<213> Homo sapiens

<400> 81

acatttcgga taatcatcca atagttg 27

<210> 82

<211> 24

<212> DNA

<213> Homo sapiens

<400> 82

aagtagttgg acttccaggt cgcc 24

<210> 83

<211> 17

<212> DNA

<213> Homo sapiens

<400> 83

ccgtggcctt agctgtg 17

<210> 84

<211> 21

<212> DNA

<213> Homo sapiens

<400> 84

ctgctggatg acgtgagtaa a 21

<210> 85

<211> 24

<212> DNA

<213> Homo sapiens

<400> 85

tctctctttc tggcctggag gcta 24

<210> 86

<211> 25

<212> DNA

<213> Homo sapiens

<400> 86

aaatgttaac aaatgtggca attat 25

<210> 87

<211> 20

<212> DNA

<213> Homo sapiens

<400> 87

aacaatgcct ccactccaaa 20

<210> 88

<211> 20

<212> DNA

<213> Homo sapiens

<400> 88

tccacacaac accaggactt 20

<210> 89

<211> 22

<212> DNA

<213> Homo sapiens

<400> 89

tgaaaactac ccctaaaagc ca 22

<210> 90

<211> 21

<212> DNA

<213> Homo sapiens

<400> 90

tatccaagac ccaggcatac t 21

<210> 91

<211> 21

<212> DNA

<213> Homo sapiens

<400> 91

tagattcggg caagtccacc a 21

<210> 92

<211> 20

<212> DNA

<213> Homo sapiens

<400> 92

aagatgaggc agaggtccaa 20

<210> 93

<211> 20

<212> DNA

<213> Homo sapiens

<400> 93

tccagaatgt cacaggtcca 20

<210> 94

<211> 20

<212> DNA

<213> Homo sapiens

<400> 94

tgctggtaca agttgtggga 20

Claims

1. An apparatus for inferring activity of a nfkb cell signaling pathway based at least on measured expression levels of six or more target genes of the nfkb cell signaling pathway in a sample, wherein the apparatus comprises:

means for determining or receiving in said sample the level of a nfkb Transcription Factor (TF) element that controls transcription of six or more target genes of said nfkb cellular signaling pathway, said determining based at least in part on evaluating a mathematical model that relates expression levels of the six or more target genes of said nfkb cellular signaling pathway to the level of said nfkb TF element, wherein said six or more target genes are selected from the group consisting of: CCL5, CXCL2, ICAM1, IL6, IL8, NFKBIA and TNFAIP 2; and

a module that infers activity of a nfkb cellular signaling pathway based on the determined level of nfkb TF element in the sample;

wherein the inference is performed by a digital processing device using the mathematical model.

2. The apparatus of claim 1, further comprising:

a module for determining whether the NF κ B cell signaling pathway is operating abnormally based on the inferred activity of the NF κ B cell signaling pathway.

3. The apparatus of claim 2, further comprising:

it is proposed to prescribe a module for drugs that correct abnormal operation of the NF κ B cell signaling pathway,

wherein the recommendation is made only if the NF κ B cell signaling pathway is determined to be abnormally operational based on the inferred activity of the NF κ B cell signaling pathway.

4. The device of any of claims 1-3, wherein the device is used for at least one of the following activities:

performing a diagnosis based on the inferred activity of the NF κ B cell signaling pathway;

performing a prognosis based on the inferred activity of the NF κ B cell signaling pathway;

prescribing a drug based on the inferred activity of the NF κ B cell signaling pathway;

predicting drug efficacy based on the inferred activity of the NF κ B cell signaling pathway;

predicting side effects based on the inferred activity of the NF κ B cell signaling pathway;

monitoring drug efficacy;

developing a drug;

developing an assay;

path research;

staging of cancer;

clinical trial enrollment based on inferred activity of NF κ B cell signaling pathway;

selecting a subsequent test to be performed; and

a companion diagnostic test is selected.

5. The device of any one of claims 1-4, wherein the mathematical model is a probability model based at least in part on conditional probabilities relating the nfkb TF element to the measured expression levels of six or more target genes of the nfkb cell signaling pathway in the sample, or wherein the mathematical model is based at least in part on one or more linear combinations of the measured expression levels of six or more target genes of the nfkb cell signaling pathway in the sample.

6. The apparatus of claim 5, wherein the mathematical model is a Bayesian network model.

7. An apparatus comprising a digital processor configured to perform a method comprising:

inferring activity of a nfkb cell signaling pathway based at least on measured expression levels of six or more target genes of the nfkb cell signaling pathway in the sample, wherein the inferring comprises:

determining in the sample the level of a nfkb Transcription Factor (TF) element that controls transcription of six or more target genes of the nfkb cellular signaling pathway, based at least in part on evaluating a mathematical model that relates expression levels of the six or more target genes of the nfkb cellular signaling pathway to the level of the nfkb TF element, wherein the six or more target genes are selected from the group consisting of: CCL5, CXCL2, ICAM1, IL6, IL8, NFKBIA and TNFAIP 2; and

inferring an activity of an nfkb cellular signaling pathway based on the determined level of the nfkb TF element in the sample;

8. The apparatus of claim 7, wherein the method further comprises:

determining whether the NF κ B cell signaling pathway is operating abnormally based on the inferred activity of the NF κ B cell signaling pathway.

9. The apparatus of claim 8, wherein the method further comprises: prescribing an agent that corrects abnormal operation of a nfkb cell signaling pathway is suggested, wherein the suggestion is made only if abnormal operation of the nfkb cell signaling pathway is determined based on inferred activity of the nfkb cell signaling pathway.

10. The device of any one of claims 7-9, wherein the mathematical model is a probability model based at least in part on conditional probabilities relating the nfkb TF element to the measured expression levels of six or more target genes of the nfkb cell signaling pathway in the sample, or wherein the mathematical model is based at least in part on one or more linear combinations of the measured expression levels of six or more target genes of the nfkb cell signaling pathway in the sample.

11. The apparatus of claim 10, wherein the mathematical model is a bayesian network model.

12. A non-transitory storage medium storing instructions executable by a digital processing device to perform a method comprising:

13. The non-transitory storage medium of claim 12, wherein the method further comprises:

14. The non-transitory storage medium of claim 13, wherein the method further comprises: prescribing an agent that corrects abnormal operation of a nfkb cell signaling pathway is suggested, wherein the suggestion is made only if abnormal operation of the nfkb cell signaling pathway is determined based on inferred activity of the nfkb cell signaling pathway.

15. The non-transitory storage medium of any one of claims 12-14, wherein the mathematical model is a probabilistic model based at least in part on conditional probabilities relating the nfkb TF element to the measured expression levels of six or more target genes of the nfkb cellular signaling pathway in the sample, or wherein the mathematical model is based at least in part on one or more linear combinations of the measured expression levels of six or more target genes of the nfkb cellular signaling pathway in the sample.

16. The non-transitory storage medium of claim 15, wherein the mathematical model is a bayesian network model.

17. A kit for measuring the expression level of six or more target genes of the nfkb cell signaling pathway in a sample, comprising:

polymerase chain reaction primers directed against the six or more NF κ B target genes,

a probe directed against the six or more NF kappa B target genes, and

wherein the six or more NF κ B target genes are selected from the group consisting of: CCL5, CXCL2, ICAM1, IL6, IL8, NFKBIA and TNFAIP 2.

18. Kit according to claim 17, comprising the apparatus according to any one of claims 1 to 11, the non-transitory storage medium according to any one of claims 12 to 16 or a computer program comprising program code means for causing a digital processing device to perform the method as defined in any one of claims 7 to 11 when said computer program is run by the digital processing device.

19. A kit for measuring the expression level of six or more target genes of the nfkb cell signaling pathway in a sample, comprising:

one or more components for determining the expression level of six or more target genes of the NF κ B cell signaling pathway, and

the apparatus of any one of claims 1-11, the non-transitory storage medium of any one of claims 12-16 or a computer program comprising program code means for causing a digital processing device to perform the method as defined in any one of claims 7 to 11 when said computer program is run by the digital processing device, and

wherein the six or more target genes of the NF κ B cell signaling pathway are selected from the group consisting of: CCL5, CXCL2, ICAM1, IL6, IL8, NFKBIA and TNFAIP 2.

20. The kit of claim 19, wherein the one or more components are selected from the group consisting of: microarray chip, antibodies, multiple probes, RNA sequencing and a set of primers.